Invited EditorialEffects of progestogens on the postmenopausal breastB. de Lignières Service d’Endocrinologie et Médecine de la Reproduction, Hôpital Necker, Paris, France Key words: PROGESTINS, BREAST CANCER, POSTMENOPAUSE, PROGESTERONE, ESTRADIOL, ESTRONE,17b-HYDROXYSTEROID DEHYDROGENASE, HUMAN BREAST EPITHELIAL CELLS ABSTRACT
The potential for an increased risk of breast cancer linked to the use of synthetic
progestins combined with oral estrogens is one of the main putative reasons for dis-
couraging postmenopausal women from using any type of hormone replacement therapy
(HRT) for more than a few years. Because no definitive proof exists, the available epi-
demiological results can be interpreted according to what seems biologically plausible to
each investigator, including potential differences between various schedules of various
steroids in various species and in vitro models.
More than 60 years after the discovery of progesterone, the main effects of this endo- genous steroid on the physiopathology of the breast during a normal luteal phase are still Downloaded By: [Swinburne University of Technology] At: 20:51 28 January 2008 controversial. The lack of consensus on such basic knowledge concerning one of themost important targets of a natural ovarian hormone discovered in 1934 is amazing. Inthe most cited studies, nothing has been done to measure progesterone in plasma and tocorrelate the extremely disparate cytological results with extremely erratic steroid levelsat the time of surgical stress. In a recent study, with a better design, the physiological riseof endogenous progesterone during the luteal phase coincided with a drop in prolifera-tion of breast epithelial cells, which appears to be only slightly delayed in comparisonwith what is described in the endometrium. Differences in doses and schedules of treat-ments with various synthetic progestins have largely contributed to the inconsistency inclinical recommendations. Based on the analysis of proliferation markers in surgicalbiopsies from normal human postmenopausal breast tissue, it is plausible that mitogenicactivity is not identical during therapy with unopposed estrogens versus estrogens com-bined with progestogens, and is higher during HRT that combines oral conjugatedequine estrogens with medroxyprogesterone acetate than during HRT that combinestransdermal estradiol and progesterone. It is misleading to put all progestogens in thesame bag irrespective of their chemical structure, and, more important, their effect mayvary according to whether it is estrone or estradiol that is mainly accumulated in thebreast tissue. The hypothesis of progesterone decreasing the proliferative effect ofestradiol in the postmenopausal breast remains highly plausible.
Breast cancer incidence increases with age and one levels are very low, but a major role of these most breast cancers are diagnosed after the hormones in the development of the disease is menopause1 when serum estradiol and progester- Correspondence: Dr B. de Lignières, Service d’Endocrinologie et Médecine de la Reproduction, Hôpital Necker, Paris, France First, a slowing of the rate of increase in breast mostly small, well-differentiated, lymph node- cancer incidence around age 50 years is generally negative breast cancers. This may create early presented as evidence of a dependence on serum detection bias in treated women who are more levels of ovarian hormones. However, this slowed frequently screened by mammograms. The use of rate of increase affects only the recorded incidence an estrogen replacement therapy does not alter the of breast cancer diagnosis and not the breast breast cancer risk in women who are slightly over- cancer mortality. This may be partly due to the weight and therefore likely to show relatively high decrease in regular mammography screening observed after the menopause in untreated women2. When changes occur in the way that during the pivotal perimenopausal years5 and no breast cancer is diagnosed, trends in recorded inci- local synthesis of progesterone occurs after the dence rates should be interpreted with caution3. If, menopause, this endogenous hormone should not independently of mammography screening, early have a major influence on postmenopausal breast menopause actually reduces the breast cancer risk, cancer. However, despite almost 100 epidemio- and late age at menopause increases it4, then the logical studies analyzing the risk of cancer during ovarian secretion of estradiol during the peri- hormone replacement therapy (HRT), the specific menopausal years should play an especially influence of exogenous progestogens administered important role at early stages of the disease.
in combination with estrogens is still the subject Because the incidence of anovulatory cycles increases during these perimenopausal years5, theendogenous secretion of progesterone can only benegatively related to the increase of breast cancer EPIDEMIOLOGICAL STUDIES
In most studies, combined HRT users still account Second, in untreated postmenopausal women, for a small minority of the cases, selected accord- the highest residual serum estradiol (and testoster- ing to unspecified and probably variable criteria, one) levels are associated with a higher risk of breast cancer6–8. However, the serum estradiol estrogens. This selection, unrestricted to non- threshold separating the high- and low-risk hysterectomized women, weakens the power of Downloaded By: [Swinburne University of Technology] At: 20:51 28 January 2008 groups after the menopause is very low, i.e.
statistical analysis and introduces potential 3–10 pg/ml for total estradiol6,7 and 2 pg/ml for biases11. Only 4–12% of the treated populations bioavailable estradiol8, suggesting that the circu- included in US cohorts in the 1970s, 1980s and lating estrogens become far less important than 1990s used a progestin combined with estrogens, the local synthesis in breast cancer cells. Breast while the majority received unopposed estrogens4.
adipose tissue and most carcinomas acquire For example, among 2082 postmenopausal breast aromatase and 17b-hydroxysteroid dehydro- cancer patients analyzed in a recent US cohort genase activities efficient enough to synthesize study13, only 101 (4.8%) used a progestin, which estradiol locally from androgenic substrates, was added for about 10 days per month to an which is a pivotal mechanism in maintaining the estrogen. The overall relative risk (RR) of breast growth of estrogen-dependent cancers, indepen- cancer (1.3, confidence interval (CI) 1.0–1.6) was dently of serum estrogen levels9. The very small not significantly increased in this subgroup.
difference between the highest and lowest However, a harmful effect associated with the postmenopausal serum estradiol levels may simply duration of estrogen–progestin use was reported, reflect the level of aromatase activity in several based on only 18 cases (0.8%) of invasive breast tissues, but not an actual direct dependence cancer diagnosed in recent users of combined of breast cancer cells on circulating levels of £ 24.4 kg/m2. In this subgroup the RR was 1.9 Therefore, the overall risk, if any9,10, of again (CI 1.1–3.3) overall, and 1.08 per year of use raising serum estrogens in postmenopausal women is low4. It may only be relevant to women Multiplying small, selected subgroups increases with a lean body weight, likely to exhibit low the risk of results being simply due to chance aromatase activities. If these women use estrogen distribution of collected or uncollected subject replacement therapy, their breast cancer risk characteristics, and hence may be misleading11.
increases to the level observed in untreated In one study, only the sequential use of a postmenopausal women who are slightly over- progesterone-derived progestin (5.3% of cases) weight. This risk is not dose-related, and involves appeared to be associated with a significantly increased risk13. Another study showed that only studies have not yet delivered a message consistent the continuous combined use of testosterone- and clear enough to help clinicians.
derived progestins (1.9% of cases) was associatedwith an increased risk16, and in a third the riskwas similar for the use of oral estrogens alone and ENDOGENOUS PROGESTERONE
for sequential or continuous combined HRT AND HUMAN BREAST EPITHELIAL
No definitive proof exists of a potential influ- In agreement with in vitro experiments23, the ence of progestogen, and the available epidemio- endogenous surge of progesterone during the logical results can be interpreted according to luteal phase induces a down-regulation of estro- what seems biologically plausible to each investi- gen receptors in normal breast epithelial cells28. It gator17,18, including potential differences between thus seems reasonable to expect some anti- various regimens, in various species and in various estrogenic effects from progesterone. As proges- terone does not down-regulate its own receptors When seeking biological plausibility, the in breast cells, its effects here may differ from pivotal debate still concerns the effects of natural those well known in the endometrium28. Many progesterone on human breast epithelial cell pro- papers report, as an established fact, that proges- liferation. The lack of consensus on such basic terone is the major mitogen in the normal breast knowledge concerning one of the most important epithelium of premenopausal women12,15,17,18,29.
targets of a natural ovarian hormone discovered20 The studies most often cited to support this state- more than 60 years ago (1934) is amazing.
ment analyzed the proliferative activity in surgicalbreast biopsies collected on different days of themenstrual cycle30,31. Because the highest values ofthymidine index were measured in some of the PROGESTERONE AND HUMAN
women having surgery around days 21–25, a BREAST EPITHELIAL CELL
mid-luteal rise in progesterone was supposed to be PROLIFERATION IN VITRO
the main mitogenic factor. However, a consider- Because of its rapid metabolization, progesterone able intersubject variability in thymidine index Downloaded By: [Swinburne University of Technology] At: 20:51 28 January 2008 has rarely been used in in vitro studies, and even was observed during the same days of the luteal in recent studies it is frequently replaced by phase. This variability was far beyond what could various synthetic progestins21,22 with longer half be expected from technical problems28, but no lives but potentially different effects. In the few attempt was made to explain why between day 21 in vitro studies using natural progesterone, it and day 25 some patients showed high mitotic down-regulates estradiol receptors and inhibits activity and others low. Specifically, no attempt the cell proliferation stimulated by estradiol in was made to correlate thymidine index with either normal human breast epithelial cells23. Similarly, estradiol or progesterone serum or tissue levels, progesterone arrests human breast cancer cells in the G1 phase of the second cycle by up-regulating However, probably due to stress anovulation, cyclin-dependent kinase inhibitors (p21 and p27) one study measured very low serum and breast tissue progesterone levels in 40% of premeno- performed on breast tumor cell lines show a pausal patients when surgery was done during the pro-apoptotic effect of progesterone25, reproduced expected luteal phase32. Therefore, from these first by a pregnane-progestin21, while another study studies, it is impossible to know whether women shows an anti-apoptotic effect of medroxy- with a high mitotic activity during the second part progesterone acetate (MPA)26. Therefore, in vitro of their menstrual cycle are ovulatory women with studies suggest potential benefits from progester- high progesterone levels or, conversely, anovula- one in regulating human breast epithelial cell tory women with low progesterone levels.
growth. However, because large discrepancies Attempts to avoid surgery by using fine-needle appear between various synthetic progestins26,27 aspirations in one recent study33 may have been and antiprogestins at various concentrations in misleading34, because aspirations produce only various milieux, these results are still poorly pre- hundreds of epithelial cells while surgical biopsies dictive of what actually happens in the human produce the thousands required for sufficient breast in vivo12. Probably because of their increas- statistical power. Also, in the same study, the use ing complexity, and despite their use of objective of Ki-67 to replace the relatively imprecise and reproducible measurements, these in vitro thymidine index was inappropriate. This marker of the cell cycle has a short half-life of about 1 h, and produces a signal too weak to identify varia- 17b-estradiol. In comparison with placebo treat- tion when the average mitotic activity is low, as ment, 14 days of transdermal estradiol treatment is seen in normal breast epithelial cells. Ki-67 significantly increased the proliferation of normal labelling is detected in < 1% of normal breast epi- breast epithelial cells but a combination of trans- thelial cells in treated and untreated postmeno- dermal estradiol and progesterone did not, in both pausal women, which is not enough to detect a significant change during estrogen replacement inpostmenopausal women35,36, while proliferatingcell nuclear antigen (PCNA), with a longer EXOGENOUS PROGESTINS AND
half-life of about 20 h, labels 8–20% of these cells HUMAN BREAST EPITHELIAL CELL
and shows a significant increase in proliferation PROLIFERATION IN VIVO
It is plausible that various combinations of estro- Only one study, excluding anovulatory women, gens and progestogens may differently influence has measured plasma and tissue progesterone con- the proliferation of human breast epithelial cells centrations, the epithelial cell cycle using PCNA and the relative risk of breast cancer.
and apoptosis (terminal uridine deoxynucleotidyl To date, the most widely studied estrogens are nick end labelling, TUNEL) in surgical material oral conjugated equine estrogens (CEE) and estradiol. The serum and breast tissue levels of improved design, the epithelial cell growth was estrone and estrone sulfate and the estrone/ shown to be directly related to the estradiol/ estradiol ratio are far higher following oral CEE progesterone tissue ratio. This was significantly or estradiol than during physiological ovarian lower during the luteal than the follicular phase.
activity or during transdermal estradiol treat- ment40–42. The first consequence is that the daily endometrium, the slowing of the epithelial cell urinary excretion of 16OH-estrone, a metabolite cycle during the endogenous progesterone surge classified as genotoxic43, has been shown to be was slightly delayed and of less magnitude in the abnormally high in users of oral estrogens44.
Another consequence of high levels of estrone may Downloaded By: [Swinburne University of Technology] At: 20:51 28 January 2008 be a difference in progestogen-stimulated 17b-hydroxysteroid dehydrogenase activities45. The EXOGENOUS PROGESTERONE AND
balance between the two 17b-hydroxysteroid HUMAN BREAST EPITHELIAL CELL
dehydrogenase isoforms, the first reducing estrone PROLIFERATION IN VIVO
to estradiol and increasing estrogenic activity, and Few studies have tried to investigate the effects of the second oxidizing estradiol to estrone and natural progesterone administration on normal reducing estrogenic activity, may favor the synthe- human breast in vivo. Two have compared the sis of estradiol if the estrone/estradiol ratio is high effects of topical applications on the breast skin of in the epithelial cell environment. Then, the conse- gels containing either a placebo, 17b-estradiol or quence of 17b-hydroxysteroid dehydrogenase progesterone during the follicular phase of pre- activity stimulation by the progestin could be reversed if the main estrogen accumulated in surgery32,37. A third study conducted the same breast tissue is estrone instead of estradiol, which experiment in postmenopausal women38. These may be crucial for breast cancer cell proliferation9.
regimens produced different concentrations of In most epidemiological studies, CEE have been estradiol and/or progesterone within the breast used occasionally in combination with MPA4, a tissue of normal women in vivo. In these three synthetic progestin which may be different from studies, high estradiol and low progesterone tissue progesterone in its effects on breast tissue. For levels were associated with the highest mitotic example, in breast cancer cell lines, progesterone activity, measured either by mitotic figure has been shown to induce apoptosis and reduce counting32 or by PCNA labelling37,38. Tissue con- proliferation in some studies25, while MPA has centrations of progesterone similar to those been shown to do the reverse in others26. Also, measured during a normal luteal phase were con- MPA45, in contrast with progesterone46,47, has stantly associated with a lower rate of mitotic been described to stimulate the reductive 17b- activity. These studies were consistent in showing hydroxysteroid dehydrogenase isoform more than that natural progesterone alone does not stimulate the oxidative 17b-hydroxysteroid dehydrogenase epithelial proliferation, but opposes, in the short According to surgical breast biopsies conducted the androgen or estrogen receptors, rather than in postmenopausal women, the epithelial mito- the progesterone receptors, may simply predict genic activity, measured by PCNA labelling, their effects on human breast tissue in vivo has not increases similarly during treatment with either been confirmed12,27,36. The potentially opposite oral CEE36 or transdermal estradiol38. Activity effects of progestogens on human breast cell pro- increases even more so with HRT regimens com- liferation in vivo may depend primarily on the bining oral CEE and MPA36, while the addition of structure and concentration of the main estrogen, progesterone to transdermal estradiol decreases estrone or estradiol, accumulated in the breast it38. These biological results, supported by some of tissue. The hypothesis of progesterone decreasing the epidemiological surveys12–15, suggest that the the proliferative effect of estradiol in the post- HRT regimens combining oral CEE and MPA are menopausal breast remains highly plausible.
not optimal for breast tissue and should be Conflict of interest The author has served as a stopped after a few years of use17,18. Clear differ- consultant for Asta-Medica, Besins-International, ences in the effects of a progesterone-derived Bristol Myers, Hoechst Roussel, Janssen-Ortho, progestin such as MPA and of a testosterone- Pharmacia Upjohn, Schering, Shiseïdo, Solvay and derived progestin such as norethisterone or norgestrel have not been consistently established.
The possibility that the binding of progestins to References
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