Review article 745

Nomegestrol acetate/estradiol hormonal oral contraceptive and breast cancer risk Lino Del Pupa, Massimiliano Berrettab, Raffaele Di Franciad, Carla Cavalieree, Marilena Di Napolie, Gaetano Facchinie, Francesco Fioricaf, Mario Miletoc and Adolf E. Schindlerg Combined hormonal contraceptives (CHCs) contain estrogen and progestin, which can stimulate estrogensensitive and/or progesterone-sensitive breast cancer growth. Until recently, ethinylestradiol had been almost the only estrogen used for decades, and its dose has been greatly reduced over time. The first generations of birth control pills contained approximately five times more estrogen and four times more progestin than the latest contraceptives. Newer CHCs also contain steroids that more closely mimic the physiological estradiol (E2) and progesterone effects. The newer CHC formulations are thus expected to have less influence on the breast, although it is very difficult to demonstrate any difference among the recent available preparations in human studies. Recently, nomegestrol acetate (NOMAC), a neutral, nonandrogenic, progesterone-like profile progestin, has become available in combination with the ‘natural’ estrogen, E2. According to the literature, NOMAC/E2 is expected to have either a lesser stimulating effect or a neutral effect on estrogen-sensitive breast cancers. We performed an analysis of the available studies and a bibliographical review. The endocrine and metabolic

effects of NOMAC/E2 formulation might lead to a lesser breast tissue stimulation. The data reported, confirmed through clinical studies, should be considered when choosing a hormonal contraceptive, especially when breast stimulation is a concern. Anti-Cancer Drugs c 2014 Wolters Kluwer Health | Lippincott 25:745–750 Williams & Wilkins.

Introduction

Data obtained in a recent multicenter, population-based, case–control investigation [2] confirmed the results obtained over the past few years. In a multivariable analysis containing 10 different contraceptive formulations, with 50 women enrolled per formulation, breast cancer risk was not affected by any of the CHCs. The RR for women who were currently using OCs was 1.0 (95% CI 0.8–1.3) and 0.9 (95% CI 0.8–1.0) for those who had previously used them, respectively.

Combined hormonal contraceptives (CHCs) contain estrogen and progestogen (Pr) that can stimulate estrogen-sensitive and/or progesterone-sensitive breast cancer growth, but at the same time they reduce ovarian estrogen and progesterone production. The first generations of CHCs contained estrogens and Pr at higher doses and Pr derived from testosterone with androgenic effects, accounting for the slightly increased breast cancer risk reported in some of the older studies. In more recent studies, the risk has decreased because the CHCs assessed are more similar to those currently used [ethinylestradiol (EE) dosage 50%) could result in clinically relevant pharmacodynamic effects [11]. Excretion is through the urine and feces [12]. Although there has been some experience in the use of NOMAC in combination with estrogens as a hormonal replacement therapy, most of the data in the literature report on its inclusion as a component of a new contraceptive pill comprising 2.5 mg NOMAC combined with 1.5 mg E2 (Zoely). Because of its strong endometrial efficacy, and due to its high antigonadotropic activity and long elimination half-life (46 h) the contraceptive efficacy of the new pill is maintained even when dosages are missed. Furthermore, for the first time with a monophasic 24/4 regimen containing E2, the cyclical stability achieved can be compared with that obtained using pills containing EE and progestins such as levonorgestrel (LNG) or drospirenone (DRSP). The combination of NOMAC and E2 preserves the beneficial effects of estrogen, which is of unique importance in relation to the cardiovascular system.

Nomegestrol acetate/estradiol reduces breast cell proliferation A study [13] on human breast cancer cells ZR75-1 and HCC1500 incubated with equimolar concentrations showed similar proliferation with E2 and EE. In both cell lines E2 and EE elicited a significant increase in the proliferation markers and a decrease in apoptosis.

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Oral contraceptives and breast cancer risk Del Pup et al. 747

Table 1

Relevant drug interaction with nomegestrol acetate administration

Drugs Aminoglutethimide Bosutinib Cyproterone acetate Corticosteroids (systemic) CYP3A4 inducers (strong) such as deferasirox, herbsb, tociluzumab

CYP3A4 inhibitors (strong) such as rifampicine, ketoconazole Pimozide Silodosin

Annotation May decrease the serum concentration of CYP3A4 and CYP3A5 substrates Decrease the serum concentration of CYP3A4 substrates May decrease the serum concentration of CYP1A2 substrates May increase the serum concentration of corticosteroids (systemic) May increase the metabolism of CYP3A4 substrates Management: consider an alternative for one of the interacting drugs to avoid therapeutic failure of the substrate May increase the serum concentration of CYP3A4-metabolized drugs May increase the serum concentration of pimozide May increase the serum concentration of silodosin

a

Ranked risk

D: consider therapy modification X: avoid combination C: monitor therapy C: monitor therapy D: consider therapy modification. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling X: avoid combination X: avoid combination C: monitor therapy

CYP, cytochrome P450. a Risk rank: A, low; B, moderate; C, monitor therapy; D, therapy modification; and X, avoid combination; as defined by Launch Lexi-Interact Drug Interactions Program (http://www.uptodate.com/contents/drug-interaction). b Examples of herbs include: black cohosh, bloodroot, hops, iperico, kudzu, licorice, red clover, saw palmetto, soybean, thyme, wild yam, and yucca.

This study confirmed the differences existing between the Pr and depending on the regimen. Progestin addition most significantly reduced the estrogen-induced proliferation rate. Usual and extended cycles with a combined contraceptive were mimicked by incubation periods of 3 days with 1 day hormones off and continuous use, respectively. NOMAC plus E2 in the intermittent model, king cyclical pill regimen, significantly reduced breast cell proliferation (P < 0.01) compared with E2 alone. Furthermore, in the intermittent model, NOMAC showed an antiproliferative effect, whereas LNG did not; the longer half-life (50 vs. 10 h, respectively) might partly explain this. According to the global proliferative measurements, NOMAC had a similar or better antiproliferative effect than LNG and DRSP. The intermittent regimen stimulated the breast less than the continuous one and it was associated with reduced estrogen receptor a expression. Estrogens enhanced the antiapoptotic protein bcl-2, which was strongly reduced by Pr and, among them, NOMAC seemed to be one of the most effective molecules in promoting breast cell apoptosis and in reducing cell proliferation.

Nomegestrol acetate does not have breast proliferative effects Progestins may play a crucial role in the development of breast cancer. They have different abilities, inducing proliferation or inhibiting the growth of benign or malignant human breast epithelial cells dependently or independently of the effects on stromal growth factors and of E2 action. The overall agonist or antagonist effect of a certain Pr is determined by its interaction with coactivators and corepressors. The different binding affinities do not always correlate with biological response. Most of the Prs have distinct effects on different hormone receptors (estrogen, androgen, mineralocorticoid, and glucocorticoid), explaining their complex effects on breast tissue.

NOMAC is a pure Pr molecule because it binds almost exclusively to the progesterone receptor, does not interfere with androgen or mineralocorticoid and glucocorticoid receptors, and has partial antiandrogenic activity [14]. NOMAC as a 19-nor-progesterone derivative shows no estrogenic activity in several in-vitro models, and demonstrates no direct promotion of estrogen-sensitive breast cancer [15]. NOMAC is exclusively antiproliferative in breast cancer cell studies (such as MCF-7 or T-47D) and displays other antiestrogenic activity in vitro and in vivo [16–18], in contrast to 19-nor-testosterone derivatives.

Nomegestrol acetate does not stimulate progesterone receptor membrane component 1 Several in-vitro studies indicate that Pr may exert an antiproliferative effect by the activation of nuclear progesterone receptors A and B, but there are also membrane receptors. The progesterone receptor membrane component 1 (PGRMC1), highly expressed in breast cancer, may instead increase breast cancer risk [19]. PGRMC1 is able to mediate an up to 10-fold increase in proliferation when activated by testosterone-related Pr. In MCF-7 cells some Prs stimulate proliferation; among them norethisterone (NET) shows the highest proliferative effect. In studies in which NET-derived or LNGderived Pr is continuously administered, a significantly higher risk for breast cancer has been observed than for continuously administered progesterone-derived Pr [20]. To test the effects of progesterone and synthetic Pr chlormadinone acetate (CMA), desogestrel (DSG), DRSP, dydrogesterone (DYD), (LNG, medroxyprogesterone acetate (MPA), NOMAC, and NET on cell proliferation, MCF-7 and WT-12 cells were stimulated with different concentrations (0.01–1 mmol/l) [21]. In MCF-7 cells, DRSP, DSG, DYD, LNG, and NET increased the

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proliferation at 1 mmol/l. NET demonstrated the highest proliferative effect (> 20%). In WT-12 cells, the same progestin, but additionally MPA, showed a significant increase, which was much higher (30–245%) than in MCF-7 cells. Here again, NET showed the highest proliferative effect. No breast proliferative effects were found with NOMAC, CMA, and natural progesterone.

Nomegestrol acetate inhibits breast tissue estrogen biosynthesis The tumoral breast tissular concentrations of estrogens could be high (they could be even 5–45 times higher than in the plasma or in the normal tissue of hypoestrogenic women) because the breast contains all the enzyme systems necessary for the local formation and transformation of E1 and E2 from circulating precursors. NOMAC possesses a global beneficial, antiestrogenic effect on the enzymes involved in estrogen biosynthesis and metabolism. In breast cancer cells or total breast cancer tissue, NOMAC has demonstrated the following actions reducing local E2 production: (1) Inhibits estrone sulfatase [22], (2) Inhibits 17b-hydroxysteroid dehydrogenase type 1 [23], and (3) Stimulates sulfotransferase [24,25]. The breast cancer cell line MCF-7aro shows a 900-fold higher aromatase activity as it overexpresses the aromatase gene. NOMAC is an antiaromatase agent in these cells [26]. Other studies on the regulation of aromatase activity by Pr showed no effects with progesterone or Pr-like MPA, CMA, and norethindrone on various models such as human placental aromatase activity or in breast tumors [27–31].

Nomegestrol acetate/estradiol further effects NOMAC acts as a strong multidrug-resistant reversal agent in MCF-7/ADR (adriamycin resistant) cells by sensitizing their chemosensitivity to adriamycin [32]. As a result it is a promising anticancer drug to be tested in clinical trials. NOMAC/E2 as a contraceptive has less influence on surrogate markers of adrenal and thyroid function, androgens, and androgen precursors than other CHCs, such as LNG/EE [33]. Theoretically, a more neutral contraceptive should also have less influence on hormone-sensitive cancerogenesis. NOMAC seems to be a good combination with E2 regarding the oncological perspective, but it also has further advantages such as a neutral effect on glucose metabolism, which is related to breast cancer risk, and on the lipid profile. It preserves the favorable effects of E2 on blood vessel walls, such as relaxation of smooth muscle cells, vasodilatation, and capacity to inhibit platelet aggregation by enhancing the release of nitric oxide [34–36].

NOMAC absorption rapidly reaches a peak serum concentration within 2–4 h, and combined with E2 it has a prolonged elimination half-life of 46 h, much longer than most Pr, a further advantage for the stability of its beneficial effects. Hormonal contraceptives have been shown to reduce the absolute rate of any cancer among ever-users at 45 or 10 per 100 000 woman years, depending on the main or general practitioner observation dataset used, as reported in the Royal College of General Practitioners’ study of oral contraception [37]. Hannaford and colleagues stated that the balance of cancer risks and benefits, however, ‘may vary internationally, depending on patterns of oral contraception usage and the incidence of different cancers’. Therefore, using a high-EE dose together with an androgenic Pr or a combination of nonandrogenic Pr as NOMAC and a natural estrogen, E2, could make a difference. In this study the CHCs analyzed since 1968 contained 50 mg of EE (75% of patients), more than 50 mg (12% of patients) and less than 50 mg in only 10% of women, whereas 3% of patients used progestin-only pills. Hormonal contraceptives reduce cancer incidence, but in addition they also slightly reduce all-cause mortality [38]. Therefore, the above-mentioned cardiovascular, coagulation, and metabolic positive impact and the strong endometrial and ovarian inhibition of NOMAC/E2 (Zoely) contraceptive should also be considered when choosing a CHC together with a theoretical beneficial breast effect [9,12,39–42]. The very low E2 dose could rarely cause vaginal dryness in CHC users, treatable with vaginal promestriene [43]. A recent review [44] confirms that it does not increase the serum estrogen pool, even in cancer patients [45], and validates topical promestriene safety.

Conclusion

The reduced breast cancer risk of the recent CHCs is likely due to the lower estrogenic content and the Summary of beneficial breast effects of nomegestrol acetate/E2 (Zoely)

Table 2

NOMAC plus E2 significantly reduces breast cell proliferation (P < 0.01) compared with E2 alone, in the intermittent model [13] NOMAC is similar to or better than LNG and drospirenone according to the global breast proliferative measurements [13] NOMAC seems to be among the more effective progestins favoring breast cell apoptosis [13] NOMAC is a pure, strong, long half-life Pr that does not interfere with androgen or glucocorticoid receptors and can affect breast tissue proliferation [14] NOMAC as a 19-nor-progesterone derivative lacks any direct estrogenic activity [15–18] NOMAC has no breast proliferative effect in MCF-7 and WT-12 breast cancer cells overexpressing PGRMC1 [19–21] NOMAC possesses a global beneficial effect on the enzymes involved in breast estrogen biosynthesis and metabolism, reducing local estrogen-mediated proliferation: inhibition of estrone sulfatase and 17b-hydroxysteroid dehydrogenase type 1 and stimulation of sulfotransferase [22–26] LNG, levonorgestrel; NOMAC, nomegestrol acetate; PGRMC1, progesterone receptor membrane component 1.

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Oral contraceptives and breast cancer risk Del Pup et al. 749

different progestin, compared with previous generations of CHCs [41]. NOMAC has antiproliferative effects or, at least, it does not increase proliferation, in normal and breast cancer tissue [42] or in women overexpressing PGRMC1 as summarized in Table 2. Thus, recent researchers have stated that NOMAC ‘will be neutral in terms of breast cancer risk when combined with E2’ [46].

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In conclusion, although there are no clinical data confirming it, a lesser breast stimulation with NOMAC/ E2 (Zoely) is biologically plausible, and this might be an important point to consider when choosing a hormonal contraceptive.

Acknowledgements

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Conflicts of interest

There are no conflicts of interest.

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estradiol hormonal oral contraceptive and breast cancer risk.

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