Climacteric

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Progesterone, progestins and the breast in menopause treatment

A. Gompel & G. Plu-Bureau

To cite this article: A. Gompel & G. Plu-Bureau (2018) , progestins and the breast in menopause treatment, Climacteric, 21:4, 326-332, DOI: 10.1080/13697137.2018.1476483 To link to this article: https://doi.org/10.1080/13697137.2018.1476483

Published online: 01 Jun 2018.

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Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=icmt20 CLIMACTERIC 2018, VOL. 21, NO. 4, 326–332 https://doi.org/10.1080/13697137.2018.1476483

REVIEW Progesterone, progestins and the breast in menopause treatment

A. Gompel and G. Plu-Bureau Unite de Gynecologie Endocrinienne, Universite Paris Descartes Hopitaux,^ Universitaires Port Royal-Cochin, Paris, France

ABSTRACT ARTICLE HISTORY is the main risk associated with menopause (MHT). It is a hormone- Received 26 March 2018 dependent cancer. In postmenopausal women, about 80% of cases are estradiol receptor-positive. In Revised 6 May 2018 cohort studies only estradiol receptor-positive breast cancers are promoted by MHT. Different levels of Accepted 10 May 2018 risk with estrogen-only treatment and combined treatment with estrogen þ progestin are shown in Published online 1 June 2018 randomized trials and observational studies. Several non-randomized studies show a lower risk with KEYWORDS progesterone and than with synthetic progestins. Progesterone and progestin are Menopause; micronized non-selective ligands for the and bind also with other receptors, with progesterone; dydrogester- agonistic or antagonistic effects according to the structure of the molecule. Their half-life and metabol- one; proliferation; normal ism are also different, progesterone being rapidly degraded with a short half-life. These aspects will be breast tissue; breast cancer discussed in this review.

Introduction demonstrated by the increase in the risk of breast cancer in post-pubertal girls irradiated during the Hiroshima and The actions of progesterone and progestin on breast tissue Nagasaki bombing3. The main actor during this phase is are a controversial and complex subject. Data coming from estradiol. The growth of the mammary gland starts with the epidemiologic studies on breast cancer and hormone treat- initiation of estradiol secretion by the ovary at extremely low ment, biology and preclinical animal models are mostly concentrations; these are in the same range as in postmeno- driven by invalidated studies or studies in transgenic mice pause. At this time of life, there is an extreme sensitivity of which have limited similarity with the human breast. breast tissue to very low amounts of estradiol but will not be Breast cancer is one of the most multifactorial diseases, the case any time thereafter. The action of estradiol also with very high risk associated with genetic background but, depends upon the presence of pituitary growth hormone in addition, several other factors are involved with lower lev- and the production of insulin-like growth factor-1 in the els of risk. Among them, gonadal hormones throughout the mammary gland. The first menstrual cycles are most often reproductive life are clearly playing a role. However, when anovulatory. After an average of 2 years, they become ovula- 1 predicting the risk by scores such as the IBIS tool ,or tory with the secretion of progesterone. Both estradiol and by summing the known risk factors as we have done in a progesterone act to control proliferation and differentiation 2 previous publication , about 40% of the risk remains of the luminal epithelium with progressive development of unpredictable. lobulo-alveolar structures. The mammary epithelium develops We will review herein the current knowledge on progesto- into a bilayered ductal structure, consisting of an outer basal gen and the breast in relation to menopause hormone ther- myoepithelial layer of cells and an inner luminal cell layer apy (MHT). which is present among ducts and alveoli. During puberty, the growth of the epithelium but also the stroma and the Physiology adipose tissue, frequently an important component of the breast, is mostly dependent on estradiol. The maximal differ- The breast is a target tissue for gonadal hormones. Its main entiation will be only reached after the first full-term preg- function is to provide lactation. In the last generations of nancy by the successive and synergic action of estradiol, women, this function has become of short duration for progesterone and prolactin. If this event occurs early in life, most women. it can be protective against the risk of breast cancer through During puberty, breast tissue undergoes a rapid and differentiation protecting from potential DNA damage and important proliferation in order to bring the mammary gland mutations. Inversely, a late first full-term pregnancy can be from a state of a few cells to a pre-adult organ. This rapid associated with an increasing risk of breast cancer by pro- growth occurs within 3–5 years. Such a rapid growth can moter effects of hormones on precancerous/cancerous thus be associated with errors in DNA replication if some car- pre-existing lesions. During pregnancy, the high level of hor- cinogens are present during that period. This was clearly mones initially causes the mammary gland to increase in

CONTACT A. Gompel [email protected] Universite Paris Descartes, Hopitaux^ Universitaires Port Royal-Cochin, Paris, 75014, France ß 2018 International Menopause Society CLIMACTERIC 327 size, with an increasing number of lobulo-alveolar structures; hormone-dependent breast cancer, it remains unclear and its a phase of differentiation then follows in order to establish real place is still to be understood7,8. Recent data suggest a lactation at the end of pregnancy. A rapid and important role for this pathway in BRCA1-deficient models9. Most of the apoptosis will follow the end of pregnancy and lactation. The data came from mice knock-out models and cannot yet be process of lactation leads to the terminal state of differenti- extrapolated to the human. It is important also to know that ation of breast tissue. It is rather difficult to decipher the role denosumab is an antagonist of RANK and reported to be of progesterone in normal breast. It is a complex effect which beneficial in bone metastasis prevention. Other develop- is fully driven to produce lactation. This includes increasing ments are suggested through the recent studies but not yet the production of progenitor cells from stem cells in order to validated. An intervention trial in women carriers of the provide a rich and functional ductal and lobulo-alveolar BRCA1 mutation is planned to evaluate the potential development. prevention of breast cancer by denozumab (presentation by Most of the studies conducted to understand the effect of Penninger at International Society of Gynecological estradiol and progesterone upstream from cancer have been Endocrinology Congress, Florence, 2018). developed in animal models or in vitro. Relevant models to Progesterone acts through specific nuclear receptors. The study the physiopathology of breast disease are scarce. None PR has two isoforms with different activities. In addition, of the animal models are similar to the human mammary there are several forms of membranous receptors, progester- gland, whereas most of the published studies in the field one membrane component (PGRMC) 1 and 2, mPRa, mPRb have been done in murine models and extrapolated to the and mPRc, non-classical G protein receptors, members of the human breast. There are some major differences in the physi- progestin and adipoQ receptor (PAQR) family10. ology of the mice mammary gland and the human one. In Most of the data obtained so far concerning breast cancer particular in rodents, between pregnancies, only ductal struc- are in vitro data on estrogen receptor (ER)-negative cell lines, tures are kept, the lobulo-alveolar development being only but their presence in biopsies of breast cancer and (in limited concomitant to pregnancy. It is thus mandatory for breast studies) their possible relationship with feeding to increase the volume of the mammary gland by a sensitivity11 suggest that they could play a distinct role from rapid proliferation. The human gland, however, contains per- the classical nuclear PR in breast cancer progression. manent lobulo-alveolar structures between pregnancies. It Interestingly, they can be activated differently by progester- was nevertheless shown that the lobules gained more differ- 12 one and synthetic progestins . entiated aspects with the occurrence of pregnancy, with more developed lobules. Each pregnancy increases the level of differentiation of lobules. Recent advances have been Clinical studies gathered from cells obtained from normal breast tissue by Studies on the level of proliferation during the menstrual mammoplasty; these cells were analyzed by the FACS tech- cycle have shown that there is a peak of proliferation during nique and different markers, which allowed the separation of fractions of cells between supposed stem cells (difficult to the luteal phase followed by apoptosis. The breast tissues specifically demonstrate their nature), luminal progenitors came from women operated for benign breast diseases in most of the cases where the ovulation was not validated. and mature luminal epithelial cells. These cells were selected 13 by some markers and the effects of estradiol, progesterone, The study from Longacre and Bartow analyzing the breast or antiprogestogen were studied for their prolif- from autopsies of premenopausal women and correlating eration. From these studies, it was shown that progesterone with an endometrial biopsy was the most convincing due to acted indirectly to promote the proliferation of emerging its excellent methodology. Endometrial biopsies confirmed luminal progenitor cells which do not contain the progester- ovulation in those patients. They reported a peak of prolifer- one receptor (PR) but by a paracrine effect. Progesterone ation in luminal cells which was maximal during the late – 13 induced the receptor activator of NF-jB ligand (RANKL). The luteal phase (days 23 25) . These studies concluded that RANKL receptor RANK is present in the progenitor cells, and progesterone was responsible for the peak in proliferation in thus the RANKL/RANK system could control their prolifer- the luteal phase. ation4,5. It was also reported that the incidence and onset of However, different conclusions on the proliferative effects acetate (MPA)-driven breast cancer in of progesterone could be obtained from three interventional mice were associated with a massive induction of RANKL in studies. These studies had a similar design, evaluating mammary gland epithelial cells; inactivation of RANK in these the effect on proliferation of topical administration of cells prevented MPA-induced epithelial proliferation, impaired estradiol ± progesterone in luminal cells in normal breast expansion of stem cells, and sensitized the cells to DNA dam- tissues in women before plastic surgery. The results were age-induced cell death4,5. However, no comparison between congruent showing that estradiol increased proliferation, the potencies of MPA and progesterone was provided. progesterone alone did not change it and, during Furthermore, was not able to reverse or oppose estradiol þ progesterone treatment, the proliferation was – the effect of progesterone. These observations, mostly reversed to the level of controls14 16. Progesterone concen- reported in murine models, remain to be confirmed in tration was measured in the tissue and found to be humans. In mice, it is clear that progesterone regulates the increased, validating the local impact of progesterone. RANK/RANKL system in order to provide a proper lactation Another study was conducted in 71 postmenopausal process6. Concerning the relation between RANK/RANKL and women randomized between two menopause treatments: 328 A. GOMPEL AND G. PLU-BUREAU

Table 1. Proliferation and level of expression of the anti-apoptotic protein bcl-2 in normal breast tissues from women treated with conju- gated equine estrogens (CEE) þ medroxyprogesterone acetate (MPA) or estradiol (E2) þ progesterone (P)17. Proliferation: Ki67 Anti-apoptotic protein (bcl-2) Treatment Baseline Treatment p Baseline Treatment p E2 þ P 3.1% (0–21.5%) 5.8% (0–39%) NS 49% (0–100%) 27% (0–80%) NS CEE þ MPA 1% (0–4%) 10% (0–55%) 0.003 46% (0–90%) 27% (0–80%) NS NS, not significant. conjugated equine estrogen (CEE) þ MPA or transdermal Risk of breast cancer with MHT estradiol þ progesterone. Biopsies were performed at baseline Estrogens versus combined MHT and after 2 months of treatment. Proliferation measured by Ki67 was significantly increased only in the CEE þ MPA arm Most published epidemiological studies, but not all, indicate (Table 1). This study is of importance since it was conducted an increased risk of invasive breast cancer with long-term in conditions of menopause treatment similar to its clinical combined MHT including a synthetic progestogen, with a use. Its limitation was, however, the relative low number of lower risk in women receiving unopposed estrogen (reviewed biopsies analyzed. It is, nevertheless, very informative on the in references 25 and 26). The only randomized trial available difference between MPA and progesterone and correlates is the Women’s Health Initiative (WHI) study. In women with very well with the results from observational studies17. a uterus, 16 608 postmenopausal women were randomized to a continuous combined MHT (CEE 0.625 mg þ MPA 2.5 mg).The combined treatment was associated initially with Epidemiology a non-significant trend towards an increased risk of breast cancer (hazard ratio (HR) 1.26, adjusted 95% confidence inter- It is freely admitted that breast cancer is hormone-depend- val (CI) 0.83–1.92), compared with non-users after a mean fol- ent. Reproductive factors are associated with the risk of low-up of 5.2 years27. In another randomized trial of the WHI, breast cancer. What is unclear is whether ovulatory cycles or 10 739 women without a uterus were randomized with CEE anovulatory cycles are those with a maximal risk. In two alone or placebo. The active-treatment group showed a trend large, prospective studies, the Nurses’ Health Study (NHS) towards a reduced risk of breast cancer (HR 0.77, adjusted and the European prospective investigation on nutrition and 95% CI 0.57–1.06) after an average follow-up of 6.8 years28. cancer (EPIC), progesterone levels were not associated (NHS) In the subsequent publications of the WHI, the relative risk or had a negative relation (EPIC) with the risk of breast can- (RR) of breast cancer in the combined MHT trial became just cer, whereas, in both studies, the level of androgen was posi- significant (HR 1.25, 95% CI 1.07–1.46) and in the CEE-only 29,30 tively associated with breast cancer18,19. An increase in trial decreased significantly (HR 0.77, 95% CI 0.62–0.95) . androgen level is associated with features of polycystic ovar- Furthermore, in the recent update on the follow-up of ian syndrome, and thus this observation suggests that it is women included in the two trials, looking at mortality from anovulation which is more often a risk factor, but this view different causes, the WHI reported that, in the combined trial, – has been controversial in the literature20,21. the breast cancer mortality HR was 1.44 (95% CI 0.97 2.15); – Insights from contraception suggest that, in premeno- for CEE-alone users, the HR was 0.55 (95% CI 0.33 0.92). All- cause cancer mortality was not affected by hormone therapy pausal women, progestin in contraception does not increase 31 the risk of breast cancer22. In premenopausal women, using use in long-term follow-up in any group . It remains unclear why CEE should be protective against breast cancer. One of progestogen for another indication than contraception the possible explanations could be that, in those women between the age of 40 and 50 years, the French cohort study without a uterus, the prevalence of obesity was high (40% E3N observed no increase in the whole population but a sig- were obese). Since one of the benefits of MHT is to decrease nificant increase in women who used any progestogen for at insulin resistance, which is a risk factor for breast cancer, it least 4.5 years23. Dose, sequence and indications were not could be through this mechanism. Another hypothesis is that available. Despite the fact that some risk factors were taken CEE contains more than 200 compounds; some are estro- ‘ ’ into account, i.e. breast biopsy, mastosis (from radiology genic and other anti-estrogenic. The last hypothesis is that, reports which are not reliable), it remains possible that some since women included in the WHI were far from menopause, other risk factors related to the medical indication for the introducing estrogens late after the menopause could induce treatment were present. It is also a hypothesis that, with a pro-apoptotic effect, based on in vitro study in breast can- increasing age, breast tissue does not react in the same way cer cells (MCF-7 cells) deprived of estrogens32. We are per- as that from younger women. In addition, in another French sonally skeptical about that hypothesis: women without study on a smaller cohort, but in which indications and types breast cancer do not receive aromatase inhibitors, so breasts of treatment and regimen were known, it was shown that containing aromatase in the adipose and breast tissues are normethyltestosterone derivatives at high dose, in women at never deprived of estradiol. It is also important to know that risk for breast cancer, were associated with a decrease in the there is no trial which has randomized women with or with- relative risk of breast cancer. The beneficial effect was out a uterus in the same trial and compared estrogen alone increased with longer duration of treatment24. and combined treatment in the same trial. The two CLIMACTERIC 329 populations of the WHI and their clinical characteristics might the study from Lyytinen and colleagues, based on registers be different and this could at least in part explain the differ- and reporting on 221 551 postmenopausal women using ent results. In particular, the prevalence of oophorectomy is MHT, showed a RR of 1.22 (95% CI 0.83–1.72) for use of different between both populations. In a recent letter to up to 5 years41. In a UK database, similarly, JAMA, Hickey and colleagues asked about the impact of Schneider and colleagues did not observe any increase in the oophorectomy on breast cancer risk33. The answer from RR with dydrogesterone (Table 2)43. Manson and colleagues was that the prevalences of oophor- ectomy were similar in the CEE-alone group and the placebo How can we explain the different levels of risk? group and thus this does not explain the lower risk with 34 estrogen alone . This does not solve the question of the dif- Progestins such as progesterone are not selective for PR as ferent characteristics in both trials. The risk associated with ligand. They are able to bind and behave as or CEE alone in the WHI was indeed different from the results antagonist on androgen receptors (AR), mineralocorticoid of breast cancer risk and estrogen only in the NHS, reporting receptors (MR), and glucocorticoid receptors (GR); further- an increased risk after long-term use for more than 10–15 more, several norsteroids are partially metabolized in estro- 35 years . CEE was the predominant estrogen used in this genic derivatives with low affinity for the ER. Breast tissue cohort study. The characteristics of the patients were defini- contains large amounts of GR, AR and MR. Interestingly, PR tively different since the women in the NHS were leaner and and GR are closely related and bind to the same response closer to menopause. It was suggested that treating women element in the promoters and enhancers of target genes. at distance from menopause is associated with a reduced risk We have shown that the active form of GR, phosphorylated of breast cancer. In women with time from menopause to on serine 211, was abundant in luminal cells and that gluco- hormone initiation (gap time) less than 5 years compared corticoids were proliferative and anti-apoptotic in normal with women with longer gap times, the HR is 0.89 (95% CI breast cells44. MPA is a strong glucocorticoid agonist as well 0.66–1.20) compared with a HR of 0.65 (95% CI 0.48–0.89), as an AR agonist. Progesterone is anti-androgenic and has but the interaction was not statistically significant (p inter- only a mild activity on GR, probably without any clinical sig- 36 action 0.13) . nificance45. We have reported that MPA and progesterone have different properties in normal human breast and breast cancer cells due to the glucocorticoid potency of Role of progestogen: progesterone versus progestins MPA44. The role of the androgenic or anti-androgenic Observational studies have reported a different risk of breast potencies is also likely to be involved in driving different cancer in women treated with progesterone/dydrogesterone levels of risk. According to the phenotypes of breast cancer, or synthetic progestins. Micronized progesterone was practic- GR, AR and MR can be involved, with an unpredictable ally used only in France in the past, but has become used effect. Publications on GR report an opposite relation more and more in other countries world-wide thanks to the between survival and GR expression in ER-positive and results of studies from the last decade. The pregnane deriva- ER-negative breast cancers46. In ER-negative breast cancers, tive, called retroprogesterone or dydrogesterone, has some high GR expression was associated with a poor prognosis47. properties in common with micronized progesterone. It is a However, these studies looked at the expression of total GR. weak progestogen, with a lower affinity than progesterone We have observed that the expression of total GR does not for PR, but a longer half-life through its metabolite, 20a-dihy- correspond to the activated form of the receptor48, suggest- drodydrogesterone. It is devoid of androgenic and estrogenic ingthatmoredataareneededontheroleofglucocorti- effects. There are now four studies, two from France, one coids in breast cancer. In addition, the impact of GR and AR from the UK and one from Finland, reporting no or lower risk may vary according to the phenotype and the grade of – of breast cancer with these two compounds37 41. The French breast cancer. We also reported a loss of expression of the cohort study E3N reported, in successive publications, that GR active form only in triple-negative cancers from BRCA1 combined hormone therapy with micronized progesterone mutation carriers48. AR is also associated with different (RR 0.9, 95% CI 0.7–1.2) or dydrogesterone was not associ- types of breast cancer and possibly with a worse prognosis, ated with any increase in the risk of breast cancer, whereas so that trials for an evaluation of benefit of synthetic progestins were associated with a significant treatment are ongoing, notably in triple-negative can- increase in the RR of 1.4 (95% CI 1.2–1.7)37,38. In a more cers49–51. In addition to the binding to various steroid recent follow-up of the cohort, it was reported that, with an receptors, the metabolism of progestin and progesterone increased duration over 5 years of use (mean use 8.7 years), could also modify the potencies through different half-lives the RR increased even with micronized progesterone and and bioavailabilities45. dydrogesterone (1.31, 95% CI 1.15–1.48), whereas it was 2.02 Another level of complexity is that some reports have (95% CI 1.86–2.26) with synthetic progestins42. The risk disap- shown that there is interplay between different steroid peared as soon as the treatment was stopped and also hormone receptors in hormone-dependent cancer cells52. decreased rapidly in the group of women who used synthetic Furthermore, there are some ligand-independent activations progestins. In a case–control study in a French population, of PR through its phosphorylation. Another difference similar results were reported (Table 2) for micronized proges- pointed out, in a recent extensive review on progestogen terone and dydrogesterone up to 5 years of use. Similarly, and breast cancer53 in normal luminal breast cells, is that 330 A. GOMPEL AND G. PLU-BUREAU

Table 2. Principal studies on the risk of breast cancer and menopause hormone therapy (MHT) with micronized progesterone (P) or dydrogesterone (DYD). Mean follow-up Study Population (years) Risk of breast cancer Fournier38 Cohort study; 80 377 French postmenopausal 8.1 Estrogen alone: RR 1.29 (95% CI 1.02–1.65) women, mean age 53.1 years Estrogen þ P: RR 1.00 (95% CI 0.82– 1.22) Estrogen þ DYD: RR 1.16 (95% CI 0.94–1.43) Estrogen þ synthetic progestins: RR 1.69 (95% CI 1.50–1.91) Espie39 Cohort study; 4949 French women, 2.5 Without MHT 0.70% mean age: 64.2 years, women with MHT; E2 alone 0.28% 60.6 years, women without MHT E2 þ P 0.40% E2 þ synthetic progestin 0.94% No increase in risk Cordina-Duverger40 Case–control study; 1555 French women: E2 alone: OR 1.19 (95% CI 0.69–2.04) 739 cases, 816 controls. Mean age of cases: E2 þ P: OR 0.80 (95% CI 0.44–1.43) 35–54 years (16.5%); 55–64 years E2 þ synthetic progestin: OR 1.57 (95% CI 0.99–2.49) (47.0%); >65 years (36.5%). Mean age of E2 þ nortestosterone derivative: OR 3.35 (95% CI 1.07–10.4) controls: 35–54 years (17.6%); 55–64 years (43.6%); >65 years (38.7%) Schneider43 Case–control study; 1261 cases and 6.0 E2 þ DYD: OR 0.68 (95% CI 0.38–1.20) 7566 controls; mean age 51.3 years CEE þ , 2–4 years: OR 1.50 (95% CI 1.11–2.04); 5 years: OR 1.34 (95% CI 0.71–2.54)a E2 þ NET, 2–4 years: OR 1.19 (95% CI 0.86–1.63); 5 years: OR 2.85 (95% CI 1.87–4.36) CEE þ MPA: OR 0.78 (95% CI 0.50–1.20) Significantly less breast cancer with DYD Lyytinen41 221 551 postmenopausal women using E2 transdermal vs. oral: no difference MHT from register, 6211 cases E2 þ NET: increase with duration: 3–10 years, RR 1.34 (95% CI 1.17–1.51); 5–10 years, RR 2.03 (95% CI 1.88–2.18); >5 years, RR 3.15 (95% CI 2.44–4.00) E2 þ MPA: 3–10 years, RR 1.27 (95% CI 1.09–1.48); 5–10 years, RR 1.64 (95% CI 1.49–1.79); >5 years, RR 1.90 (95% CI 1.07–3.07) E2 þ DYD: 3–5 years, RR 1.22 (95% CI 0.83–1.72); 5–10 years, RR 1.13 (95% CI 0.49–2.22); >5 years, no cases and very few controls In NET group: RR with continuous treatment > sequential aBased on five cases NET, ; MPA, medroxyprogesterone acetate; DYD, dydrogesterone; CEE, conjugated equine estrogens; E2, estrogen/estradiol; OR, odds ratio; RR, relative risk. the levels of ER and PR are much lower than in breast can- in normal breast tissue. In breast cancer cells, however, ER/PR cer cells. Furthermore, as shown by Russo and colleagues54, are constitutively there and PR could thus be active on prolif- it is not the ER-positive, PR-positive luminal cells that prolif- eration/apoptosis. Nevertheless, a randomized trial reported erate in normal tissue but the ER-negative, PR-negative that the injection of hydroxyprogesterone prior to surgery for cells; the proliferative signals are transducted in a paracrine node-positive breast cancer was associated with a survival manner. In addition to RANKL/RANK pathways (see above), benefit58. The recent publication from the same cohort of þ amphiregulin and Wnt 4 are controlled by estradiol pro- patients analyzing the genes associated with the treatment gesteronetoinduceproliferationandthesecompounds shows that progesterone controlled cellular stress and nega- 53 then act on ER-negative, PR-negative cells . In breast can- tive regulation of inflammatory response, which could con- cer cells containing ER/PR, hormones act on them directly tribute to better clinical outcome59. The immunomodulatory to control proliferation and apoptosis. Cross-talk exists role of progesterone is well known but has been poorly between ER and PR in breast cancer cells and, according to explored in breast cancer so far60. a recent paper, progesterone could redistribute estradiol signaling to other sets of genes than when progesterone is absent55. In summary, progesterone acts differently in normal breast Conclusions tissue and breast cancer cells. There are no data from clinical From the information gathered from clinical trials, estrogen- trials showing that progesterone is associated with a definite only treatments, indicated only in hysterectomized women, increase in the relative risk of breast cancer. carry a lower risk than combined treatments. Progesterone and dydrogesterone appear to carry a lower risk of breast Progesterone alone as a treatment for cancer than synthetic progestogen and could thus constitute climacteric symptoms the first line of treatment. Progesterone alone can also be used to treat vasomotor 56,57 symptoms and sleep disorders . There are no data on the Conflict of interest The authors report no conflict of interest. The risk of a progesterone-alone treatment in postmenopausal authors alone are responsible for the content and writing of this paper. women. From what is known in physiology, PRs are induced by estradiol. We can thus guess that, in the absence of estra- diol treatment, progesterone cannot act through PR, at least Source of funding Nil. CLIMACTERIC 331

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