The WHO claims estrogens are 'carcinogenic': is this true?

Estrogens are in the list of carcinogenic chemicals from the World Health Organization (WHO). However, estrogens require additional factors such as stromal factors or progestogens to increase the ratio of proliferation/apoptosis for initiation of replication errors and consequent mutations to occur. These mutations require at least 5-10 years to develop into clinically detectable cancer, whereby this review is focused on breast cancer. The US National Cancer Institute highlighted a second mechanism of carcinogenicity: certain estrogen metabolites are capable of inducing DNA damage, even in low concentration. They can be assessed in the tissue and circulation. However, those deleterious reactions require excessive unrestricted oxidative cell stress, for example in industrial areas with heavy pollution. We have shown that this can be avoided using transdermal instead of oral estradiol treatment, especially important in smokers. The spectrum of metabolites is also influenced by other exogenous factors such as nutrition, physical activity and certain diseases. Reduction of breast cancer risk as demonstrated in the Women's Health Initiative (WHI) was explained by pro-apoptotic estrogen effects working after a certain 'time gap'. In addition, certain estrogen metabolites are carcinoprotective, if no genetic polymorphisms would impair their beneficial activities. Thus, since additional factors are required for both main pathways of carcinogenicity and because estrogens can even have carcinoprotective effects, we cannot agree with the statement from the WHO.

PGRMC1 promotes triple-negative breast cancer cell growth via suppressing ferroptosis.

OBJECTIVE: Triple-negative breast cancer (TNBC) is the most malignant form of breast cancer with increasing incidence and mortality worldwide. The progesterone receptor membrane component-1 (PGRMC1) is a well-identified hormone receptor with unknown functions in TNBC. The current study aims to explore the involvement of PGRMC1 in regulation of glutathione metabolism and ferroptosis during development of TNBC, providing new therapy options for TNBC patients. METHODS: Bioinformatic analysis, cell proliferation assay, western blot assay and other biochemistry methods were performed in TNBC cells. RESULTS: Our results revealed that the expression of PGRMC1 is higher in TNBC than the other subtypes of breast cancer. Interestingly, as an iron binding protein, increased PGRMC1 expression in TNBC cells leads to resistance to ferroptosis inducer. On the contrary, silenced PGRMC1 expression enhanced sensitivity of MDA-MB231 cells to Erastin. Mechanistically, overexpression of PGRMC1 decreased the intracellular free iron concentration, which was reduced by AG205 treatment. CONCLUSIONS: PGRMC1 increases the possibility of TNBC development through binding to intracellular iron and suppressing ferroptosis, providing the molecular basis of combined treatment for TNBC.

Primary choice of estrogen and progestogen as components for HRT: a clinical pharmacological view.

Prescribing hormone replacement therapy (HRT) requires consideration of the selection of its two components, the estrogen and the progestogen. In terms of the estrogen, the decision is mainly whether to use estradiol (E2) or conjugated equine estrogens (CEE). These are the components needed to efficiently treat climacteric symptoms or/and prevent osteoporosis, currently the only labeled indications. There is still controversy regarding the adequate dosages comparing E2 and CEE; however, the consensus is that the differences in the efficacy of E2 and CEE are not a real issue. Therefore, other criteria have to be used. The first reason to add the progestogen is to avoid the development of endometrial cancer (i.e. to achieve 'endometrial safety'). Any available 'fixed-combined' HRT preparation has to be tested for sufficient endometrial efficacy, because the first question the health authorities ask before product registration relates to endometrial safety. We can generally rely on the endometrial safety of these fixed-combined products. However, it could be that we want to use 'free' combinations, which are necessary if we use transdermal E2 (patches, gel, spray), but also to individualize schedules, for example when treating bleeding problems. The question here is how to attain knowledge about the endometrial efficacy of the different progestogens and how to monitor therapy. We will try to answer these two questions from a 'clinical pharmacology' point of view, as a discipline which preferably considers pharmacological properties, but also relating to clinical practice, to achieve individualized therapy with optimal efficacy, best tolerability and minimal risks.

E2 + norethisterone promotes the PI3K-AKT pathway via PGRMC1 to induce breast cancer cell proliferation.

OBJECTIVE: This study aimed to find evidence that progesterone receptor membrane component 1 (PGRMC1) promotes estradiol (E2) + norethisterone (NET)-induced breast cancer proliferation through activation of the phosphatidylinositol-3-kinase (PI3K)-AKT pathway. METHODS: PGRMC1-mediated breast cancer cellular proliferation and phosphorylation of PGRMC1 were studied using wild-type (hemagglutinin [HA]-tagged) MCF-7 cells, which were stably transfected with expression vector containing HA (MCF-7-HA cells), PGRMC1 (MCF-7-PGRMC1 cells) and Ser181 point mutated PGRMC1 (MCF-7-PGRMC1-S181A cells). Bioinformatics, cell proliferation, western blot, isobaric tags for relative and absolute quantitation (iTRAQ)-based RNA sequencing, real-time quantitative polymerase chain reaction (RT-qPCR) and cell cycle in vitro assays were performed to indicate the function of PGRMC1 and its possible mechanisms in breast cancer. RESULTS: NET + E2 elicited a significant proliferation in MCF-7-Vec at 10-6 M and 10-10 M, respectively. MCF-7-PGRMC1 did increase the phosphorylation of AKT or ERK, which can be blocked by treatment with casein kinase 2 (CK2) inhibitor quinalizarin or in MCF-7-PGRMC1-S181A cells. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the PI3K-AKT pathway is upregulated in MCF-7-PGRMC1 cells. Importantly, upregulation of the PI3K-AKT pathway mainly through promotion of cell cycle regulation strongly promoted cell proliferation in MCF-7-PGRMC1 cells. CONCLUSIONS: CK2 is involved in phosphorylation of PGRMC1 at S181. The mechanism for the action of PGRMC1 for mediating proliferative progestogen effects obviously starts with promotion cell cycle regulation, and then activation of the PI3K-AKT pathway.

First live birth in China after cryopreserved ovarian tissue transplantation to prevent premature ovarian insufficiency.

OBJECTIVE: This article reports the first live birth after cryopreserved ovarian tissue transplantation to prevent premature ovarian insufficiency in China. METHODS: A patient with myelodysplastic syndrome received ovarian tissue cryopreservation before hematopoietic stem cell transplantation, and six ovarian cortex strips were thawed and transplanted into her peritoneal pocket 2 years later. RESULTS: Pregnancy occurred spontaneously 27 months after grafting, and a healthy girl was born at 38 weeks gestation. Until now, the child has developed normally without any major diseases. CONCLUSIONS: We report the first live birth resulting from ovarian tissue cryopreservation and transplantation in China.

Genitourinary syndrome of menopause in Chinese perimenopausal and postmenopausal women.

OBJECTIVE: The aim of this study was to investigate genitourinary syndrome of menopause (GSM) in a large cohort, analyzing the dependency on age and menopausal status and possible differences between non-hysterectomized and hysterectomized women. METHODS: Data were assessed by validated questionnaires, collected over 2 years for all eligible women attending our 'Menopause Clinic' from 31 Chinese provinces. Simple and unconditional logistic regression analysis was used with adjustments by all analyzed factors. RESULTS: A total of 4063 women (mean age 50.53 ± 6.57 years), 2107 perimenopausal and 1956 postmenopausal, were included. Almost all GSM symptoms were more frequent and severe in postmenopausal women. GSM was more frequent in hysterectomized women compared to non-hysterectomized women. Independent of menopausal status, low sexual interest (92.78%), urinary incontinence (91.65%) and vaginal dryness (91.60%) were the top three GSM symptoms. Most severe were low sexual interest (21.01%), vaginal pain (20.10%) and decreased sexual pleasure (17.13%). Prevalence and severity of GSM were not related to age, but were related to menopausal status and increased with time since menopause. CONCLUSIONS: Within 2 years, more than 4000 women with GSM traveled from all over China to our specialized clinic, indicating the great importance of GSM. Hysterectomy can increase the risk of GSM, and GSM symptoms increase from perimenopause to postmenopause and with an increase of time since menopause, pointing to the dependency on the loss of ovarian function.

First pregnancy in China after ovarian tissue transplantation to prevent premature ovarian insufficiency.

OBJECTIVE: This article reports the first case of pregnancy after frozen-thawed ovarian tissue transplantation to prevent iatrogenic premature ovarian insufficiency in China. METHODS: Ovarian tissue cryopreservation was performed in a patient with myelodysplastic syndrome (MDS) before multi-agent chemotherapy and hematopoietic stem cell transplantation. Two years later, she showed complete remission from MDS, and six frozen-thawed ovarian tissue strips were transplanted into the peritoneal pocket. RESULTS: The patient's ovarian activity was restored 3 months after transplantation, and pregnancy occurred spontaneously 27 months after grafting. Until now, the pregnancy has progressed for 30 weeks, and the repeated ultrasound showed normal fetal development. CONCLUSION: This is the first pregnancy resulting from ovarian tissue cryopreservation and transplantation in China.

Ovarian tissue cryopreservation and transplantation prevents iatrogenic premature ovarian insufficiency: first 10 cases in China.

OBJECTIVE: The aim of this study was to report on the first 10 cases of ovarian tissue cryopreservation (OTC) and retransplantation (OTCT) in China. METHODS: A retrospective descriptive study was performed of 10 Chinese women with different diseases undergoing OTC/OTCT in the first specialized center in China. Patients' ovarian function and fertility were followed up. RESULTS: The 10 cases included five cases of cervical cancer and one case each of endometrial cancer, breast cancer, rectal cancer, myelodysplastic syndrome, and aplastic anemia, respectively. The average age at OTC was 33.70 years; the time from OTC to OTCT was 15 months. The average number of transplanted ovarian tissue pieces was 4.9, with 9.5 pieces remaining cryopreserved. The OTCT position for nine cases was in a right-sided peritoneal pocket of ovarian fossa, and for one patient was in bilateral pockets. The average time from OTCT to restoration of ovarian function was 3.4 months. One year after OTCT, all ovaries were still functioning normally. In the first case, the function now remains preserved for more than 3 years. So far, the woman who wishes to conceive has no pregnancy. CONCLUSION: Regarding ovarian function, OTC and OTCT were successful and reliable in China's first cryobank. We expect to perform more retransplantations in the near future, which will add to the global data.

PGRMC1 can trigger estrogen-dependent proliferation of breast cancer cells: estradiol vs. equilin vs. ethinylestradiol.

Objective: Previous studies have shown that progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer tissue can predict a worse prognosis for breast cancer patients. Moreover, we demonstrated that PGRMC1 can increase the proliferation of progestogens. However, the role of PGRMC1 in terms of estrogen-induced proliferation and comparing different estrogens is still unclear. Methods: Non-transfected and PGRMC1-transfected T-47D cells were stimulated with estradiol (E2), with equilin (EQ), or with ethinylestradiol (EE) at 1, 10, and 100 nmol/l. Increase of proliferation was compared with a control (without estrogens) and with the estrogen-induced stimulation in empty vector cells vs. PGRMC1-transfected cells. Results: The empty vector cells showed significant proliferation (12-15%) with all three estrogens only at the highest concentration, with no relevant differences between the estrogens. PGRMC1-transfected cells showed about three-fold higher proliferation (29-66%), whereby E2 elicited the strongest and EE the lowest proliferating effects, significantly lower compared to E2 and also compared to EQ. No significant differences were seen between E2 and EQ. Conclusions: PGRMC1 increases strongly the estrogen-dependent breast cell proliferation. The proliferating effects of EE may be lower compared to E2 and EQ. This could have importance in comparing hormone therapy and contraception. Thus, PGRMC1 not only could predict the risk using progestogens but also of different estrogens.

Benefit-risk profile of black cohosh (isopropanolic Cimicifuga racemosa extract) with and without St John's wort in breast cancer patients.

Endocrine therapy in breast cancer survivors can cause severe 'climacteric' symptoms, which may compromise therapy adherence. To determine whether such symptoms can be treated with herbal medication containing black cohosh in the form of isopropanolic Cimicifuga racemosa extract (iCR) alone or in fixed combination with St John's wort (Hypericum perforatum [HP]) (iCR + HP), a systematic literature search was conducted. Results were viewed in relation to experimental data and metabolism of endocrine therapies. Most breast cancer survivors receiving endocrine therapy experienced reductions in climacteric symptoms under iCR/iCR + HP. Tamoxifen's interference potential may be countered by using higher iCR doses or iCR + HP. No estrogen-like effects at the breast or on hormones were seen. After breast cancer, even if receiving tamoxifen, patients using iCR/iCR + HP had significantly increased recurrence-free survival rates compared to non-users. These results are substantiated by experimental data demonstrating antiproliferative and anti-invasive effects of iCR in breast cancer cells and enhancement of the antineoplastic effects of tamoxifen. There are no known clinical interactions for iCR and HP with endocrine therapies. The HP extract used in iCR + HP did not exhibit any clinically relevant interaction potential. In conclusion, with its positive benefit-risk profile, iCR/iCR + HP may offer a safe non-hormonal therapeutic option for breast cancer survivors receiving endocrine therapy.

Ovarian tissue cryopreservation for patients with premature ovary insufficiency caused by cancer treatment: optimal protocol.

Objective: Premature ovary insufficiency is frequent after chemotherapy/radiotherapy in cancer patients. Ovarian tissue (OT) cryopreservation and later retransplantation, the routine method in Europe, has recently been implemented at the first center in China. We investigated the protective effect of the antioxidant N-acetyl-l-cysteine (NAC) during the decisive freezing-thawing steps. Methods: Fifteen OT samples were obtained from each of 13 cancer patients prospectively and randomly assigned to a control group and four groups with different NAC concentrations (Group 1, 0 mM NAC; Group 2, 0.5 mM NAC; Group 3, 1 mM NAC; Group 4, 5 mM NAC; Group 5, 25 mM NAC). After thawing, the follicle viability, DNA fragmentation, levels of reactive oxygen species (ROS), and total antioxidant capacity (TAC) were evaluated. Results: OT cryopreserved and thawed with 25 mM NAC (Group 5) has the lowest proportion of apoptotic stroma cells, but the worst follicle viability. The other four groups show similar anti-apoptosis and good follicle viability. Group 4 presented the lowest ROS and highest TAC levels. Conclusions: OT cryopreserved and thawed in medium supplemented with 5 mM NAC shows the highest antioxidant and lowest ROS capability, good apoptotic parameters, and follicle viability. Our results need to be confirmed in larger patient cohorts prior to being accepted as a standard protocol.

The first family group of α1-AT-P in the world with repeated hematomas: 10-year follow-up.

This case report describes the first 10-year follow-up report worldwide of a patient with the genetic variation alpha-1-antitrypsin-Pittsburgh mutation (α1-AT-P). The mutation was confirmed in a 16 year-old Chinese girl after she presented with repeated hematomas, and the mutation with bleeding tendency was also verified in her father. α1-AT-P is a spontaneously occurring autosomal dominant point mutation of α1-antitrypsin, in which methionine-358 is substituted by an arginine derivative. α1-AT-P cases are extremely rare, with only eight reported worldwide. Consequently, there is insufficient experience in the diagnosis and treatment of α1-AT-P. We followed up and reviewed the last 10 years of treatment of a young patient who suffered from repeated life-threatening hematomas, underwent emergency surgery five times, and had her ovaries removed in her twenties to avoid ovulation hemorrhage. The purpose of this article is to raise the awareness of α1-AT-P mutation and to improve its prognosis, especially in female patients.

Treatment of vaginal atrophy with estriol and lactobacilli combination: a clinical review.

In recent years, a vast quantity of clinical data has been accumulated on the pathophysiology of symptomatic vulvovaginal atrophy (VVA)/genitourinary syndrome of menopause (GSM) in peri- and postmenopausal women and on the treatment options for these conditions. Guidelines from several societies have recently been updated in favor of VVA/GSM vaginal therapy with the lowest possible doses of estrogens. The combination of a vaginal ultra-low dose of 0.03 mg of estriol (E3) and lyophilized, viable Lactobacillus acidophilus KS400 (0.03 mg-E3/L) is a unique product with a dual mechanism of action supporting not only the proliferation and maturation of the vaginal epithelium, but also restoration of the lactobacillary microflora. It has been demonstrated efficiently to establish and maintain a healthy vaginal ecosystem. Use of this combination considerably improves the clinical signs and symptoms as well as the quality of life of menopausal women suffering from vaginal atrophy. This combination therapy is well tolerated with a low overall incidence of side-effects and negligible estriol absorption. Based on recent scientific evidence and current treatment guidelines, the 0.03 mg-E3/L combination could be considered one of the options for the treatment of symptomatic vaginal atrophy in aging menopausal women.

Case report of the first successful cryopreserved ovarian tissue retransplantation in China.

Ovarian tissue cryopreservation and retransplantation has been offered as a fertility preservation approach for over a decade. At least 130 live births have been reported after frozen-thawed ovarian tissue transplantation worldwide. The first International Fertility Protection Center in China was established in 2015. Until now no live birth has been reported. However, we are able to report the first Chinese successful retransplantation of cryopreserved ovarian tissue (September 2016) in a woman with squamous cell cervical carcinoma. Restoration of ovarian endocrine function was shown in the third month after transplantation, and after 21 months of follow-up the transplants are still active and maintaining good function. This first report of successful retransplantation represents a milestone in the field of fertility preservation in China.

Dependency of cardiovascular risk on reproductive stages and on age among middle-aged Chinese women.

OBJECTIVE: To assess the 10-year cardiovascular risk in middle-aged Chinese women living in the same community and the impact of reproductive aging and age. METHODS: This was a cross-sectional study in the Yuetan Community of Beijing. Data on lifestyle habits, prevalence and treatment of chronic diseases with significance for cardiovascular disease (CVD) development were collected by interview. CVD risk factors were assessed by physical examination and laboratory tests. The 10-year cardiovascular risk was calculated using the Framingham 10-year risk score. STRAW +10 criteria were used for the stages of reproductive aging. RESULTS: A total of 536 women, aged 40-60 years, were enrolled. The incidences of hypertension, dyslipidemia, abdominal obesity, glucose intolerance and diabetes were 32.6%, 45.7%, 65.5%, 37.9% and 10.1%, respectively. After adjustment, the incidence of hypertension and diabetes increased with age and with reproductive aging. Dyslipidemia and glucose intolerance were only associated with age. Abdominal obesity was related neither to age nor to reproductive aging. The 10-year cardiovascular risk ranged from 1% to 24.8%; 11.6% of women had a moderate or high Framingham 10-year risk score. CONCLUSIONS: CVD risk factors were frequent and more than 10% of the women were at moderate or high risk of developing cardiovascular disease within the next 10 years. To our knowledge, this was demonstrated for the first time in middle-aged Chinese women. Thus, women should maintain a healthy lifestyle and physicians should monitor them to prevent CVD.

Systematic indirect comparison of ospemifene versus local estrogens for vulvar and vaginal atrophy.

In the absence of a direct head-to-head study, we performed an indirect historical comparison of ospemifene 60 mg (Senshio®) vs. local vaginal estrogens in moderate or severe vulvar and vaginal atrophy (VVA). A literature search was carried out of clinical efficacy/safety trials of local vaginal estrogens in VVA approved in Europe. For efficacy comparison, studies had to be placebo-controlled and of 12 weeks' duration. For safety comparison, studies had to be ≥40 weeks' duration. Efficacy endpoints were the difference between active and placebo in change from baseline to week 12 for symptoms, vaginal pH, and maturation value (MV). Safety endpoints were endometrial safety, breast safety, thrombosis, and adverse events. The 12-week improvement over placebo in symptom score was not different for ospemifene 60 mg and 17ß-estradiol 10 µg and for ospemifene 60 mg and estriol gel. After 12 weeks, the percentages with vaginal pH <5.0 and <5.5 were better for ospemifene 60 mg than 10 µg 17ß-estradiol. Week-12 pH changes were comparable with estriol pessaries or gel and ospemifene 60 mg. The 12-week MV improvements over placebo were similar or better with ospemifene 60 mg compared with 10 µg 17ß-estradiol and with estriol pessaries or gel. There was no increased vaginal bleeding, endometrial hyperplasia, or carcinoma (including breast cancer) relative to placebo and no signal for increased risk of venous thromboembolism with ospemifene 60 mg or 10 µg 17ß-estradiol, but the confidence intervals for both products do not exclude an increased risk. This historical indirect comparison suggests that ospemifene 60 mg has an efficacy, safety, and tolerability profile comparable to or better than local vaginal estrogens in the treatment of VVA.

Use of cyproterone acetate/ethinylestradiol in polycystic ovary syndrome: rationale and practical aspects.

INTRODUCTION: Polycystic ovary syndrome (PCOS) is a common, heterogeneous disorder characterised by hyperandrogenic skin symptoms, irregular menstruation and subfertility, increased risk of endometrial malignancy, and increased risk of preventable diseases associated with metabolic syndrome. Cyproterone acetate (CPA) 2 mg, combined with ethinylestradiol (EE) 35 µg, is indicated for the treatment of moderate to severe acne related to androgen-sensitivity (with or without seborrhea) and/or hirsutism, in women of reproductive age. OBJECTIVES: To review the present knowledge about PCOS and summarize the role of CPA/EE in the care of patients suffering from this condition for the practitioner. METHODS: Experts with clinical interest and experience in treating symptoms of androgen excess performed a non-systematic review to provide updated information regarding the use of CPA/EE in patients with PCOS. RESULTS: Polycystic ovary-related hyperandrogenic skin symptoms are effectively treated by CPA/EE, reducing not only the symptoms but also their negative impact on quality of life and mental health. Proven additional benefits for these patients include the treatment of menstrual irregularities and reduction in endometrial cancer risk. Possible benefits include preservation of fertility. Treatment increases the risk for venous thromboembolic complications. The nature of other metabolic and cardiovascular long-term effects i.e., whether positive or negative, are still to be investigated. CONCLUSIONS: Cyproterone acetate/ethinylestradiol provides effective treatment for PCO-related hyperandrogenic skin symptoms. This efficacy and additional benefits related to menstrual irregularities and endometrial cancer risk, have to be weighed against the risk of venous thromboembolic complications based on an individual benefit/risk evaluation.

The pattern of lipids and lipoproteins during the menopausal transition in Chinese women.

Objective To investigate changes in levels of lipids and lipoproteins in Chinese women during perimenopause and postmenopause as primary study endpoints, for the first time including lipoprotein(a). Methods The retrospective study was performed in 1015 women without hormone therapy aged 34-76 years from 20 provinces of China who visited the Beijing Obstetrics & Gynecology hospital. Menopausal status was defined by the criteria of the 2011 Stages of Reproductive Aging Workshop. Results Levels of total cholesterol, triglycerides and low density lipoprotein (LDL) cholesterol increased and that of high density lipoprotein (HDL) cholesterol decreased in the postmenopausal compared to the perimenopausal group. In the women with body mass index (BMI) ≥ 25 kg/m(2), total cholesterol and LDL cholesterol increased, HDL cholesterol decreased and changes in triglyceride levels were not significant. In the women with BMI < 25 kg/m(2), the increase in triglyceride levels during the transition was significant. Changes in lipoprotein(a), apolipoprotein A1 and apolipoprotein B were not significant. Comparing the groups with BMI ≥ 25 kg/m(2) vs. BMI < 25 kg/m(2), only the differences for apolipoprotein A1 and for triglycerides were significant. Triglycerides correlated positively with follicle stimulating hormone and BMI, and total cholesterol correlated positively with follicle stimulating hormone and age (all p < 0.05). Conclusions Some changes in lipids can be related to menopausal status, some to increasing age, some to both; especially triglycerides and apolipoprotein A1 were found also to be related to BMI. Surprisingly lipoprotein(a) did not change either with increasing age or during the transition despite known possible interference with estrogenic status.

Impact of smoking on estrogenic efficacy.

Depending on the type, duration and intensity of cigarette smoking, the efficacy of endogenous and exogenous estrogen can be reduced or completely cancelled. Not only does smoking diminish the beneficial effects of estrogen on hot flushes and urogenital symptoms and its positive effects on lipid metabolism, but smoking also can reduce estrogen's ability to prevent osteoporosis and perhaps also cardiovascular diseases. This is mainly caused by dose-dependent elevated hepatic clearance, partially in conjunction with lower estrogen levels, and has been demonstrated so far only with oral estrogen applications. Compensation for the failure of therapeutic action should not be made by increasing the dose in smokers since this might result in the production of potentially mutagenic estrogen metabolites associated with a higher risk of breast cancer. Since the favorable effects of estrogens seem to be not lost in smokers when estrogens are applied transdermally, this route should be preferred in smokers. The most important conclusion from the data presented is that the effects of smoking are very complex and dependent on a multiplicity of factors, so that different types of clinically relevant negative effects must be expected. Women who continue to smoke despite all warnings should be informed that smoking, in addition to all its other negative effects, can also jeopardize the success of hormone replacement therapy.

Estrogen as a new option for prevention and treatment of breast cancer ­ does this need a 'time gap'?

Due to experimental and clinical data, the hypothesis has been raised that a 'time gap' is necessary to achieve 'carcinoprotection' by estrogen therapy in postmenopausal women, possibly also in combination with certain ('neutral') progestogens. As the mechanism, apoptotic effects are discussed, which, however, would only work after long-term estrogen deprivation. Based on this hypothesis, in general, an early initiation of menopausal hormone therapy would increase the risk of breast cancer, in sharp contrast to the beneficial cardiovascular effects, only protective within the 'window of opportunity' directly after menopause. However, other mechanisms are possible which could work without a time gap, leading to a decreased risk of breast cancer or even being carcinoprotective compared with no treatment. For example, within estradiol metabolism, carcinoprotective enzymes can be upregulated and protective estradiol metabolites can be produced, as shown, for example, especially in women with balanced nutrition and physical activity. In addition, it has to be considered that a long time is needed to see any clinical effects based on the biological mechanisms which may start early after estrogen exposure. Thus, more research and studies are needed to prove the 'gap hypothesis', and it may be that estrogen is beneficial for a woman at any time of her life.