differential effects of various progestogens on metabolic risk factors for breast cancer

ORIGINAL ARTICLE

Differential effects of various progestogens on metabolic risk factorsfor breast cancer

CARLO CAMPAGNOLI, CHIARA ABBA, SIMONA AMBROGGIO,

MARIE ROSA LOTANO, & CLEMENTINA PERIS

Unit of Endocrinological Gynecology, ‘Sant’Anna’ Gynecological Hospital, Turin, Italy

(Received 17 May 2007; accepted 5 September 2007)

AbstractBiological and epidemiological findings suggest that metabolic factors – insulin, insulin-like growth factor-I (IGF-I) and sexhormone-binding globulin (SHBG) – are involved in the development and promotion of breast cancer. Estrogens,particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin andIGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oralestrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolicfactors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest thatnatural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins –with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins couldpossibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency,interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant.These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer riskthrough their negative influence on metabolic factors cannot be rejected.

Keywords: Breast cancer, progesterone, progestins, hormone therapy, insulin, insulin-like growth factor-I, sex hormone-bindingglobulin

Introduction

Recent randomized controlled studies [1,2], and most

observational studies, indicate that administration of

oral estrogens alone in menopausal women does not

increase breast cancer risk [3–9], or does so only

modestly [10–15]. In contrast, randomized controlled

[16,17] and most observational studies indicate that

the addition of synthetic progestins to estrogen

increases the breast cancer risk much more than

estrogen alone [18]. However, a study in a French

cohort suggests that when natural progesterone or

dydrogesterone is added to estrogen, the risk of breast

cancer is not increased compared with the use of

estrogen alone [19,20]. This finding is consistent with

in vivo data suggesting that progesterone does not

have detrimental effects on breast tissue [21].

The reasons for the increase in breast cancer risk

associated with the use of most of the synthetic

progestins are not clear. Different mechanisms may

be involved, depending on the kind of progestin.

Based on their chemical structure, progestins differ

or could differ from progesterone, and from one

another, in various ways: pharmacokinetics and

pharmacodynamics, potency, non-genomic interac-

tions with membrane binding sites, genomic inter-

actions with the two isoforms of the progesterone

receptor (PRA and PRB), and binding to other

members of the nuclear receptor superfamily

[22,23]. In particular, progestins endowed with

androgenic (or glucocorticoid) activity negatively

influence the metabolic factors that increase breast

cancer risk, while estrogens, especially oral estro-

gens, have favorable effects on these factors [18].

The objective of the present paper is to review

metabolic risk factors for breast cancer, and how

they are influenced by estrogens and the various

progestins.

Correspondence: C. Campagnoli, S.C. Ginecologia Endocrinologica, Ospedale Ginecologico Sant’Anna, ASO OIRM-S.Anna, corso Spezia 60, I-0126 Torino,

Italy. Tel: 39 3472379609. Fax: 39 0113134798. E-mail: [email protected]

Gynecological Endocrinology, October 2007; 23(S1): 22–31

ISSN 0951-3590 print/ISSN 1473-0766 online ª 2007 Informa UK Ltd.

DOI: 10.1080/09513590701585037

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Metabolic factors increasing breast cancer risk

The main metabolic factors involved in the develop-

ment and promotion of breast cancer are insulin and

insulin-like growth factor-I (IGF-I), while sex hor-

mone-binding globulin (SHBG) is inversely related.

Their actions are summarized in Figure 1.

Insulin

The key metabolic alteration, due to genetic and

nutritional factors, is resistance to insulin action on

carbohydrates (insulin resistance or reduced insulin

sensitivity), with consequent hyperinsulinemia [24].

Insulin resistance, hyperinsulinemia and high

blood glucose are associated with increased risk of

breast cancer [24–37]. Most epidemiological studies

have found that non-diabetic women in the highest

quartile of insulin or C-peptide levels have an

increased risk of developing breast cancer (Table I).

In a prospective study of patients with early-stage

breast cancer, fasting insulin level was directly

associated with cancer recurrence and death [38].

Moreover, a pooled analysis of six cohort studies

suggested a risk increase (1.25; 95% confidence

interval (CI) 1.19–1.3) in patients with type 2

diabetes [36]. Insulin, by itself or synergistically with

estrogens, can directly stimulate the proliferation of

cancer cells; an action probably mediated by the

IGF-I receptor [36]. High insulin levels may also

have indirect actions by increasing the liver produc-

tion of IGF-I, decreasing some IGF-binding proteins

(IGFBPs) and SHBG, and stimulating the produc-

tion of androgens (Figure 1) [24,39–41].

Insulin-like growth factor-I

Circulating IGF-I derives mainly from the liver [42].

Its production is stimulated by growth hormone

(GH) and facilitated by an affluent nutritional status

(particularly a high consumption of protein) and by

insulin level. IGF-I bioavailability is regulated by

IGFBPs, also produced in the liver. Levels of

IGFBP-1 and IGFBP-2, which decrease IGF-I

bioavailability, are inversely correlated with blood

insulin levels [43]. IGF-I is highly homologous to

insulin. The IGF-I receptor shares 55% homology

with the insulin receptor. Activation of the IGF-I

receptor by IGF-I activates the same proteins and

pathways that are activated by insulin and the insulin

receptor [36]. IGF-I has potent mitogenic and anti-

apoptotic effects on breast cancer cells. The mito-

genic effect is synergistic with that of estrogens [44–

47]. In particular, estradiol increases the number of

IGF-I receptors, and IGF-I is necessary for maximal

activation of estrogen receptors. Furthermore, both

estradiol and IGF-I cooperate in inducing the

expression of the genes necessary for maximal cell

proliferation [45], while estrogen and insulin/

IGF-I differentially regulate cMyc and cyclin D1

in a cooperative manner to stimulate cell cycle

progression [48].

Recent meta-analyses of a number of epidemiolo-

gical studies (mostly prospective studies) found that

premenopausal women in the highest quartile of

IGF-I, and also IGFBP-3 (which is produced by the

liver under GH stimulation and acts as a reservoir of

IGF-I), have an increased risk of developing breast

cancer (Table II) [49–51]. In contrast, a consistent

Figure 1. Metabolic factors favoring the development and promotion of breast cancer (IGF-I, insulin-like growth factor I; SHBG, sex

hormone-binding globulin).

Progestogens and metabolic risk factors for breast cancer 23

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effect was not observed in postmenopausal women.

However, one prospective study found a relationship

between IGF-I levels and breast cancer risk in

menopausal women receiving hormone replacement

therapy (HRT) [34], while another found a similar

relationship in overweight menopausal women [28].

Moreover, a recent study from the large cohort of the

European Prospective Investigation into Cancer and

Nutrition (809 cases/1564 controls) showed an

increased risk for the highest quartile of both IGF-I

(odds ratio (OR)¼ 1.38; p for trend¼ 0.01) and

IGFBP-3 (OR¼ 1.44; p for trend¼ 0.01) in post-

menopausal women [52].

Sex hormone-binding globulin

SHBG is also produced by the liver, and its

production is inhibited by insulin and IGF-I [24].

Low SHBG levels are a risk factor for breast cancer in

postmenopausal women [53,54]. All prospective

studies consistently showed that, in postmenopausal

women, SHBG levels are inversely related to the risk

of developing breast cancer (Table III) [54–57].

SHBG specifically binds testosterone and, with lower

affinity, estradiol. The principal consequence of low

SHBG is that levels of free (bioavailable) testosterone

are increased. Breast cancer cells and surrounding

stromal cells can aromatize androgens into estrogens.

High levels of free testosterone have been identified

as a risk factor for breast cancer both before [58] and

after [59] menopause. SHBG also decreases the

bioavailability of the more active estrogens; more-

over, through a specific receptor on the membrane of

estrogen-sensitive breast cancer cells, SHBG could

have an antiestrogenic, antiproliferative effect

[53,60].

Overall, these data indicate that metabolic factors

play a crucial role in augmenting the effect of

estrogens on breast tissue and breast cancer cells.

Effects of exogenous estrogens on metabolic

risk factors for breast cancer

Estrogens, particularly if administered orally, are able

to counteract metabolic factors that increase the risk

of breast cancer.

Table I. Risk of breast cancer with the highest quartile of insulin resistance markers.

Reference Type of study

Women with/without

breast cancer (n)

Menopausal

status

Risk excess

(95% confidence interval)

Insulin

Del Giudice et al. (1998) [30] Case–control 99/99 Pre 3.72 (1.3–10.4)

Jernstrom et al. (1999) [31] Case–control 45/393 Post 1.0 (0.9–1.0)

Muti et al. (2002) [28] Case–control* 144/503 Pre 1.7 (0.7–4.1)

Kaaks et al. (2002) [34] Case–control* 513/987 Post 0.59 (0.3–1.2)

Mink et al. (2002) [33] Case–control* 187/7894 Pre/post 1.01 (0.5–1.8)

Lawlor et al. (2004) [26] Case–control* 147/3690 Post 1.35 (1.0–1.8)

C-peptide

Yang et al. (2001) [32] Case–control* 143/143 Pre 2.9 (1.1–8.0)

Keinan-Boker et al. (2003) [35] Case–control* 149/333 Post 1.3 (0.7–2.7)

Schairer et al. (2004) [29] Case–control* 185/159 Post 1.5 (0.7–3.0)

Verheus et al. (2006) [37] Case–control* 1141/2204 550 years 0.7 (0.3–1.8)

50–60 years 1.1 (0.5–2.1)

460 years 1.7 (0.9–2.9)

*Nested within prospective cohorts.

Table II. Risk of breast cancer with the highest quartile of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding

protein-3 (IGFBP-3) (meta-analysis).

Reference

IGF-I IGFBP-3

Studies (n)

Cases/

controls

Odds ratio

(95% confidence interval) Studies (n)

Cases/

controls

Odds ratio

(95% confidence interval)

Premenopausal

Renehan et al. (2004) [49] 6 660/1193 1.93 (1.38–2.69) 5 584/1088 1.96 (1.28–2.99)

Shi et al. (2004) [51] 7 779/1306 1.38 (1.13–1.69) 4 620/921 1.42 (1.15–1.74)

Sugumar et al. (2004) [50] 7 764/1471 1.74 (0.97–3.13) 6 668/1366 1.60 (0.84–3.02)

Postmenopausal

Renehan et al. (2004) [49] 5 672/1131 0.95 (0.62–1.33) 4 367/648 0.97 (0.53–1.77)

Shi et al. (2004) [51] 9 911/1552 1.02 (0.77–1.36) 5 451/741 1.23 (0.97–1.56)

24 C. Campagnoli et al.

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Insulin

The effects of estrogen administration on glucose

homeostasis are complex and sometimes conflicting

[61]. In general, while the estrogen deficiency due to

the menopause is associated with deterioration in

glucose homeostasis, estrogen replacement at phy-

siological doses restores glucose homeostasis and

insulin sensitivity, with a reduction in circulating

insulin levels [61–64]. The decrease in insulin level is

more abrupt when estrogens are used in women with

diabetes [64,65].


Estrogen replacement therapy (ERT) reduces circu-

lating IGF-I levels, mainly via a hepatocellular effect.

This decrease is more abrupt and more constant

when oral ERT is used (hepatic first-pass effect);

several studies have shown a 20–40% decrease in

IGF-I levels. Most of these are small, longitudinal

studies [66]; however, a reduction in IGF-I has been

confirmed in a large cross-sectional study [67].

Transdermal estradiol, at the currently used doses,

does not cause a variation in mean IGF-I levels [66].

The IGF-I modifications induced by estrogen

administration depend on basal IGF-I values. When

oral estrogens are used, the decrease in IGF-I is

greater in women with higher basal levels [68]; with

transdermal estradiol, women with higher basal levels

tend to show a decrease in IGF-I, while women with

lower basal levels tend to have an increase [66].

According to one study [69], oral ERT also

decreases IGFBP-3 levels, either directly (via inhibi-

tion of IGFBP-3 synthesis by Kupffer cells) or

indirectly (faster clearance due to a reduction in the

synthesis of IGF-I). However, data on the effect of

oral ERT on IGFBP-3 levels are not consistent; some

studies have shown a 10–15% decrease [70,71],

while others reported no variations [72–75] or even

an increase [76]. This is in contrast to an approxi-

mately 30% decrease in IGF-I seen in all these

studies [69–76]. Moreover, via hepatocellular actions

(amplified by the hepatic first pass), oral ERT causes

a two- to threefold increase in IGFBP-1 levels

[70,71,74], which results in a reduction in IGF-I

bioavailability.

The reduction in IGF-I during oral ERT observed

in most studies is not a consequence of a reduction in

GH stimulation. Indeed, oral estrogen administra-

tion is followed by a sharp increase (50–250%) in

GH levels, while with transdermal estradiol the GH

increase is lower and less constant [66]. Most of the

GH increase occurs as a result of reduced negative

feedback inhibition of IGF-I on GH secretion [77].

This strongly suggests that the modifications in the

IGF-I system induced by oral ERT cause a decrease

in bioactivity of circulating IGF-I.


Oral estrogens, through their hepatocellular effects

(accentuated by hepatic first pass), induce a sharp

increase (100–250%) in circulating SHBG

[53,75,78].

Metabolic and hepatocellular effects

of progestogens

Progestogens, especially those endowed with andro-

genic activity, tend to oppose the metabolic and

hepatocellular effects of estrogens.

Insulin

The consequences of the addition of progestogens to

estrogens on glucose homeostasis are difficult to

pinpoint because findings are sometimes controver-

sial, partly due to the restricted number of women in

the more sophisticated studies.

Even though a recent meta-analysis does not show

a difference in calculated insulin resistance (home-

ostasis model assessment index) between unopposed

and combined treatment [64], progestogens tend to

reduce insulin sensitivity. This effect seems to be

stronger when the androgenic 19-nortestosterone

derivatives, levonorgestrel or norethisterone acetate

(NETA), are used [63], and depends on dosage

[79,80] and the mode of administration (transdermal

NETA, or even oral NETA added to transdermal

estradiol, has little impact [81,82]). Medroxyproges-

terone acetate (MPA) is slightly androgenic, but also

has glucocorticoid activity [22,23]. These activities

account for the decrease in insulin sensitivity

observed by most studies (particularly those per-

formed with the euglycemic hyperinsulinemic clamp)

[83–87], but not all [88,89]. The 30% reduction in

new-onset diabetes observed in four randomized

controlled trials using conjugated equine estrogens

(CEE) plus MPA [64,84,88–90] was possibly not

due to a reduction in insulin resistance [86,87].

Indeed, the most relevant marker could simply be

the insulin level. According to some studies [71,84],

Table III. Risk of breast cancer with the highest level of sex

hormone-binding globulin in postmenopausal women (case–

control studies within prospective cohorts).

Reference

Women

with/without

breast cancer

Odds ratio

(95% confidence

interval)

Manjer et al. (2003) [55] 173/438 0.70 (0.41–1.19)

Key et al. (2002) [54] 379/1208 0.66 (0.43–1.00)

Zeleniuch-Jaquotte

et al. (2004) [56]

297/563 0.58 (0.34–0.98)

Missmer et al. (2004) [57] 255/622 0.80 (0.50–1.30)


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but not others [64,91], MPA 10 mg interferes with

the reduction in insulin induced by estrogens. An

increase in insulin following the addition of oral

NETA 1 mg is also observed in most studies

[63,71,84,92]. Conversely, the literature consistently

shows a reduction in insulin (and C-peptide)

levels with oral estradiol plus dydrogesterone

[62,63,93,94], a progestin that is devoid of andro-

genic and glucocorticoid activity [22,23].


A differential effect of various progestins on circulat-

ing IGF-I levels was suggested for the first time by

one of our studies [95]. In this longitudinal study of

postmenopausal women treated with CEE 0.625 mg,

sequential addition of NETA 5 mg completely

reversed the 25% decrease in IGF-I levels observed

with the addition of the non-androgenic dydroges-

terone 10 mg [95,96]. We suggested that the

androgenic progestin interferes with the estrogenic

hepatocellular effect of reducing IGF-I synthesis, as

it does with other estrogenic hepatocellular effects

(e.g. increase in SHBG) [95]. Although NETA 5 mg

is a relatively high dose, even the use of 1 mg NETA,

continuously combined with oral estradiol 2 mg,

was associated, in longitudinal studies, with only a

slight (10%) decrease [97], or even with a 10%

increase [98], in IGF-I levels. In a larger longitudinal

study, the same combined preparation caused a

65% increase in IGF-I in women with basal IGF-I

levels below the median and a slight, non

significant, decrease (9%) in women with high basal

levels [99].

A differential effect of progestins, depending on

their androgenicity, has also been observed in a

cross-over study of two contraceptive pills containing

ethinyl estradiol 0.03 mg [100]. The preparation

containing the non-androgenic dienogest 2 mg

caused a 30% reduction in mean IGF-I concentra-

tions, while the pill containing the androgenic

levonorgestrel 0.125 mg caused only a 12%

reduction.

The best evidence for the interference of andro-

genic progestins on the estrogen-induced decrease in

IGF-I levels comes from two randomized cross-over

studies. In the study by Heald and colleagues [71],

the IGF-I decrease observed with CEE 0.625 mg was

partially reversed by the sequential addition of the

slightly androgenic MPA 10 mg, but it was counter-

acted to a greater extent by the addition of the more

androgenic desogestrel 0.075 mg, and almost halved

with the addition of the androgenic norethisterone

1 mg (Figure 2). In the second randomized

cross-over study [78], in contrast to the two non-

androgenic progestins cyproterone acetate and dy-

drogesterone, NETA 2.5 mg counteracted the IGF-I

decrease in women treated with CEE, and both

NETA and MPA 10 mg caused a significant increase

in IGF-I levels in women given transdermal estradiol

(Figure 3).

The fact that the slightly androgenic MPA is able

to partially interfere with the estrogen-induced IGF-I

decrease was also confirmed by a large cross-

sectional study [67] and by a longitudinal study

comparing women treated with either CEE alone or

CEE combined with MPA [101]. Chlormadinone

acetate, although non-androgenic, seems to have a

similar effect; it has been used in two longitudinal

studies in which an increase (not a decrease) in IGF-I

levels was observed during HRT [102,103]. Con-

versely, our recent studies have confirmed that

dydrogesterone does not interfere with the IGF-I

Figure 2. Effect of estrogen alone, and combined with progestins of

increasing androgenicity, on insulin-like growth factor-I (IGF-I)

and insulin-like growth factor-binding protein-1 (IGFBP-1) levels

in a randomized, triple cross-over study (n¼ 35) [71] (HRT,

hormone replacement therapy; CEE, conjugated equine estrogen

0.625 mg; MPA, medroxyprogesterone acetate 10 mg; DG,

desogestrel 75 mg; NE, norethisterone 1 mg).


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decrease induced by oral estrogens [104,105]. In a

longitudinal study of 45 postmenopausal women

given oral estradiol 2 mg with the sequential addition

of dydrogesterone 10 mg, IGF-I levels determined

during the progestogenic phase of the sixth cycle

showed a 15% decrease in women with basal levels

below the median and a 40% decrease in women

with high basal levels [104].

In the cross-over study by Heald’s group [71],

administration of estrogen alone caused a 15%

decrease in IGFBP-3 levels and a threefold increase

in IGFBP-1 levels. Both effects were opposed by

MPA, desogestrel and norethisterone, in a manner

proportional to their androgenicity [71] (Figure 2).

For IGFBP-1, a reversal of the increase induced by

oral estrogen was also observed with NETA 1 mg

[106]. This effect probably contributes to the

increase in IGF-I bioavailability [105].

In summary, some synthetic progestins reverse the

reduction in IGF-I bioactivity, due to either the

decrease in IGF-I or the increase in IGFBP-1,

induced by oral estrogens.


Androgenic progestins, and to a much lesser extent

MPA, also oppose the most typical hepatocellular

effect of estrogens, i.e. an increase in SHBG

secretion by the liver [53,78,95,107]. Once again,

this effect is not exerted by the progesterone-like

progestins, e.g. dydrogesterone [78,95] (Figure 3).

Note that 35–40% of 19-nortestosterone-derived

progestins (levonorgestrel, NETA) circulate bound

to SHBG [108]. This phenomenon, in combination

with the progestin-induced reduction of SHBG

production, results in increased levels of free andro-

gens and estrogens [108].

Differential effects of various hormone

preparations on breast cancer risk: Are

modifications in metabolic factors relevant?

Most epidemiological studies indicate that adminis-

tration of oral estrogens alone (particularly CEE)

does not increase breast cancer risk [1–9], or does so

only modestly [10–15]. The most important rando-

mized controlled trial, the CEE-only study of the

Women’s Health Initiative, even suggests a decrease

in breast cancer risk [2]. It has been hypothesized

that this may be because breast cancer cells are

susceptible to estrogen fluctuations [2]. Another

reason could be that some components of the CEE

preparation have a non-estrogenic, or even an

antiestrogenic, effect on breast tissue [109]. How-

ever, the actions of oral estrogen on metabolic

factors, especially the sharp reduction in IGF-I

bioactivity and the increase in SHBG level, could

be an important contribution to the protective

activity [110,111].

Regarding the consequences of progestin addition,

the data available up to 2005 refer only to MPA and

19-nortestosterone derivatives. These data indicated

an increase in risk, which was greater with the 19-

nortestosterone derivatives [18]. This was attributed

to the counteractive effect of androgenic progestins

on the favorable modifications of metabolic risk

factors by oral estrogens [18]. Important new data on

the consequences of progestogen addition come from

the French study based on the E3N-EPIC cohort.

This cohort included approximately 55 000 post-

menopausal teachers who were followed up with

periodic questionnaires. The first results were pub-

lished in 2005 [19]. Further results, with longer

follow-up and more detailed data, are now available

[20]. The relative risks were 1.4 with unopposed

estrogen (mainly transdermal estradiol), 1.0 with the

Figure 3. Percentage change from baseline in insulin-like growth

factor-I (IGF-I) and sex hormone-binding globulin (SHBG) levels

during treatment with estrogen alone, or combined with proges-

tins, in a randomized study (n¼19) [78] (E, estrogen; TTS,

transdermal; E2, estradiol; CEE, conjugated equine estrogen; CA,

cyproterone acetate 5 mg; DYDR, dydrogesterone 20 mg; MPA,

medroxyprogesterone acetate 10 mg; NETA, norethisterone acet-

ate 2.5 mg). *p50.05 vs. E, EþCA and EþDYDR; **p5 0.01

vs. E, EþCA and EþDYDR.


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addition of natural progesterone, 1.3 with the

addition of dydrogesterone, and 1.8 with the addition

of other synthetic progestins. The finding that

progesterone addition does not increase the risk is

consistent with the in vivo data suggesting that

natural progesterone does not have detrimental

effects on breast tissue [21], and with epidemiologi-

cal findings showing that high levels of endogenous

progesterone do not increase [112], or may even

reduce [113], breast cancer risk in premenopausal

women. The activities of dydrogesterone are very

similar to those of natural progesterone [23], so it is

not surprising that it also does not cause an increase

in risk, in contrast to the other synthetic progestins.

In France, androgenic progestins were used in only a

minority of women [19], while the most used

synthetic progestins were non-androgenic (proges-

terone derivatives or 19-norprogesterone derivatives)

or even antiandrogenic (e.g. cyproterone acetate). It

is possible that preferential prescribing of non-

androgenic or antiandrogenic HRT to women with

signs of hyperandrogenism, who are at higher breast

cancer risk [114], partly explains these findings.

However, a real association between the use of most

synthetic progestins and breast cancer risk has to be

considered. It is possible that different mechanisms

are involved for different progestins, e.g. differences

from progesterone in relation to pharmacokinetics

and pharmacodynamics, potency, non-genomic ac-

tions, binding to other steroid receptors, and inter-

action with the PRA and PRB isoforms of the

progesterone receptor. Differences in the activation

of the two progesterone receptors could be particu-

larly relevant; while PRB acts as an activator of

transcription, PRA may act as a repressor not only of

the activity of PRB, but also of that of the estrogen,

androgen and glucocorticoid receptors [22]. How-

ever, for the time being, these are theoretical

speculations. In the uncertainty surrounding this

issue, the possibility that progestins endowed with

androgenic (or glucocorticoid) activity increase

breast cancer risk via their negative influence on

metabolic factors cannot be discarded.

Acknowledgements

The authors would like to thank Professor Franco

Berrino and Ms Maria Grazia Guerrini, Department

of Preventive and Predictive Medicine, Istituto

Nazionale dei Tumori, Milan, for their precious

suggestions and kind support, and Ms Saveria

Battaglia for her skilled secretarial work.

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