Progestin Hormone Replacement Therapy Research Articles

The Correlation Between Progesterone and Mammographic Density in Postmenopausal Women: A Systematic Review of the Literature and Meta-Analysis.

Higher mammographic breast density in premenopausal and postmenopausal women is related to a higher breast cancer risk. In this review, we analyze the correlation between estrogen, progesterone, and mammographic density in postmenopausal women and clarify whether these findings are consistent across different types of mammographic breast density. We extracted data concerning mammographic density increases in the populations treated with estrogen-only hormone replacement therapy and those treated with estrogen and progestin hormone replacement therapy. Postmenopausal women treated with estrogen and progesterone regimens had a statistically significant lesser mammographic density increase than estrogen-only hormone replacement therapy regimens.

Early detection, risk factors, and prevention of endometrial cancer

BackgroundEndometrial cancer (EC) is the fourth most common female malignancy and the most common pelvic malignancy.AimTo review the current literature on early detection, risk factors, and prevention of EC.Materials and methodsThis article is based on the current, S3 Guideline of the German Society of Obstetrics and Gynecology for the “Diagnosis and treatment of women with endometrial cancer” (AWMF Registry Number: 032/034-OL; May 2022). The current literature was summarized based on systematic searches in the database Medline and Cochrane Central Register of Controlled Trials. The quality of the evidence was rated according to the 2011 Oxford classification. Recommendations and statements were formulated by a representative group using structured consensus.ResultsIn Germany, 10,860 cases of EC were diagnosed in 2018. The incidence of EC increases with age and EC is most often diagnosed in the age group of 75- to 79-year-old women. The life-time risk of EC is 2.1%. Endometrioid adenocarcinoma is the most common histological subtype of EC, characterized by its hormone-dependency. Risk-increasing factors of EC are early age at menarche, late age at menopause, long-term use of estrogens without progestogen opposition, long-term estrogen–progestogen hormone replacement therapy, tamoxifen, controlled ovarian stimulation during assisted reproduction, obesity, impaired glucose metabolism, and polycystic ovary syndrome (PCOS). There is no evidence-based screening for the early detection of EC. The most common clinical symptom of EC is abnormal uterine bleeding. Risk-reducing factors are oral contraceptives, intrauterine devices, physical activity, diet, and bariatric surgery in morbidly obese women. In addition, preventive hysterectomy may be discussed with women who have a hereditary tumor predisposition syndrome such as Lynch syndrome or Cowden syndrome, which are both associated with an increased risk of EC.

What is the association between estrogen and breast cancer?

Aim: There is a historical acceptance about the causal relationship between Estrogens and Breast cancer which has either affected the incidence rate or mortality rate of breast cancer, or could have influenced the uptake or continuation of Estrogen in Hormone Replacement Therapy (HRT). Estrogens are useful either as Estrogen-only HRT (ERT) or as combined Estrogen and Progestogen HRT. There is now a need to clearly differentiate between ERT and HRT in their consequences with regard to breast cancer. This review documents the basis of the historical causal connection and the current situation Methodology: The literature was searched with the following key words: Estrogen, Breast cancer, Estrogen receptors and Menopause;. Incidence and mortality rates of breast cancer associated with Estrogen. Randomized controlled Trials, Observational studies. Cell proliferation, cell differentiation and cell development. Results: The relationship between Estrogen & Breast Cancer with regard to incidence and mortality requires a rigorous scrutiny because: There are prenatal influences which have an impact on exposure to Xenoestrogens across the life course, starting with conception – if not before, giving possible effects on germ cells and gametes. The evidence from observational studies should be interpreted with caution because of procedural inadequacies. The evidence that should be used for care of women is that from Randomised controlled trials because they are geared to infer on cause and effect relationships. The relationship between Estrogen alone for peri-menopause and menopause shows that it does not increase the risk of breast cancer or the mortality from breast cancer. Conclusion: Estrogen alone does not increase the risk and the mortality of breast cancer. The combination of ERT with a progestogen can increase the risk of breast cancer.

Clinical Impact of Hormone Replacement Therapy on Atrial Fibrillation in Postmenopausal Women: A Nationwide Cohort Study.

Individuals with atrial fibrillation (AF), especially women, have an increased risk of stroke and death. Although hormone replacement therapy (HRT) is widely used in postmenopausal women, the association between HRT use and AF risk is unclear. We aimed to investigate the association between various types of HRT and AF. This was a population-based retrospective cohort study from The Korean National Health Insurance Service-National Sample Cohort (2004–2015). Participants were aged 45–60 years and were free from cardiovascular disease and AF at baseline. Overall, 13,452 (64.03%) women had never received HRT, 5671 (26.99%) had received HRT, and 1885 (8.98%) were currently receiving HRT. In multivariable analysis, the relative hazards for AF were significantly higher among current users (p < 0.001) and lower among past users (p = 0.069). Current users—except those using estradiol-only HRT—had significantly elevated AF risk. Among past users, only estradiol plus progestin HRT users had a reduced AF risk after adjusting for covariates (p = 0.027). Ongoing HRT posed an increased risk of AF. The degree of risk varied based on the specific type of estrogen and progestins co-administration. These findings indicate that, with respect to AF risk, oral estradiol-containing HRT is superior to HRT containing oral conjugated equine estrogen or tibolone.

CLINICAL IMPACT OF HORMONE REPLACEMENT THERAPY ON LONE ATRIAL FIBRILLATION IN POSTMENOPAUSAL WOMEN: A NATIONWIDE COHORT STUDY

Individuals with atrial fibrillation (AF), especially women, have an increased risk of stroke and death. Hormone replacement therapy (HRT) is widely used to control symptoms of menopause and treat osteoporosis in postmenopausal women. However, the association between HRT use and AF risk has been scarcely explored. Thus, we aimed to investigate the association between various types of HRT and lone AF in a national cohort of Korean menopausal women. In total, 21,023 women enrolled in the Korean National Health Insurance Service-National Sample Cohort database were included. Participants were aged 45–60 years and were free from cardiovascular disease and AF at baseline. For analysis, participants were classified into groups of HRT never users, past users, and current users, and subgroup analysis was performed according to the specific type of HRT. In the overall population, 13,458 (64.02%) women never received HRT, 5,685 (27.04%) had received HRT previously, and 1,880 (8.94%) were currently receiving HRT. In multivariable analysis, the relative hazards for AF were higher among HRT current users (hazard ratio [HR]: 1.86; 95% confidence interval [CI]: 1.26-2.75; p=0.002) and significantly lower among HRT past users (HR: 0.73; 95% CI: 0.56-0.95; p=0.021). For current users, an increased AF risk was observed for all HRT users except for estradiol-only HRT users (HR: 1.25, 95% CI: 0.40-3.90, p=0.703). For past users, reduced AF risk was observed in estradiol plus progestin HRT (comparison: HRT never users) after adjusting for covariates (HR: 0.62; 95% CI: 0.39-0.97; p=0.038). We observed that ongoing HRT posed an increased risk of AF. The degree of AF risk varied based on the specific type of estrogen and whether progestins were co-administered. These data support the assertion that HRT containing estradiol is more beneficial than other types of HRT in terms of AF risk.

Differential Genomic Interactions Drive Progesterone Receptor Isoform Specific Functions in Breast Cancer

Progesterone is critical for normal breast development and function, and has been shown to stimulate proliferation of normal breast epithelial cells by increasing stem and progenitor cell numbers. Breast cancer incidence is increased in women exposed to progesterone analogues in combined estrogen plus progestin hormone replacement therapy, but not in women taking estrogen alone. Classical progesterone signaling is mediated through the nuclear progesterone receptor (PR), which occurs as two related but functionally different isoforms, PRA and PRB. PRA and PRB are co-expressed equally in normal breast tissue but become dysregulated in breast cancer where PRA often becomes predominant. PRA predominance in breast cancer is associated with poorer outcome and higher risk of distant metastasis in tamoxifen treated patients. We show using integrated analysis of ChIP-seq, ATAC-seq and transcriptomic profiling in a breast cancer cell line model of acquired PRA predominance that: 1) PRA and PRB have different requirements with regard to chromatin accessibility; 2) PRA predominance reshapes the PR cistrome and the associated transcriptome to affect genes not normally regulated by PR when PRA and PRB are equivalently expressed, possibly through assisted loading with multiple other transcription factors; 3) Genes regulated by PR only when PRA is predominant are associated with poorer breast cancer outcome and involved in multiple cancer-associated pathways including those that regulate cell proliferation and adhesion. Our data suggest a mechanism for the poorer disease outcome seen in breast cancers with a predominance of PRA.

Embryo transfer associated with hormone replacement therapy cycles using assisted reproductive technology increases placenta accreta spectrum.

To evaluate obstetric outcomes in embryo transfer (ET) during estrogen with progestin hormone replacement therapy (HRT) cycles using assisted reproductive technology (ART). Of the 118 singleton pregnancies conceived with ART and delivered between January 2015 and December 2017, we reviewed the data of 87 cases that had information on HRT at the time of ET. Data on pregnancy outcomes included the presence of small for gestational age fetuses, hypertensive disorders of pregnancy, placenta previa (including low-lying placenta), placental abruption and placenta accreta spectrum (including placenta accreta, placenta increta and placenta percreta). We investigated the relationship between HRT cycles and adverse placental outcomes (placenta accreta spectrum, placental abruption, placenta previa, hypertensive disorders of pregnancy and small for gestational age fetuses). We then analyzed the associations that correlated with adverse placental outcomes. Patients with ET during HRT cycles were more likely to have placenta accreta spectrum. During the study period, 87 out of 118 singleton live births using ART had information on HRT (60 HRT cycles and 27 ovulation cycles). The incidence of placenta accreta spectrum was significantly higher in the HRT cycle group than in the ovulation cycle group (HRT cycle, 31.7% [19 of 60] vs ovulation cycle, 7.4% [2 of 27]; P < 0.01). The obstetric outcomes occurring in pregnancies involving HRT use may differ among ET cycles. ET during HRT cycles were associated with adverse obstetric outcomes due to placenta accreta spectrum. The potential interaction between HRT cycles and adverse placental events is novel and warrants further investigation.

Abstract P1-08-07: Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort

Abstract Background: Nuclear grade, believed to be established early in carcinogenesis, is an indicator of ductal carcinoma in situ (DCIS) prognosis. Women with high-grade DCIS have a higher risk of local recurrence compared to women with low-grade DCIS. Risk factors for DCIS overall are well-characterized but risk factors by grade are not. Given the prognostic capabilities of grade for DCIS, it is of interest to identify whether risk factors by DCIS grade differ. Methods: Among 75,630 women enrolled in the Cancer Prevention Study-II Nutrition Cohort in 1992-1993, we identified 422 who were diagnosed with low-moderate grade DCIS (i.e. grades 1 or 2) and 355 who were diagnosed with high-grade DCIS (i.e. grade 3) during follow-up through 2013. Beginning in 1997, biennial questionnaires were administered to update exposure status, including screening mammography in the previous two years. For this analysis, these questionnaires were used to partition follow-up time into approximately two-year intervals. Because screening is strongly linked to diagnosis of DCIS, contribution of person-time within a specific interval was conditional on reporting a screening mammogram in the interval prior. Multivariate joint Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for the associations of known breast cancer risk factors with DCIS overall, and with high-grade and low-grade DCIS individually. Results: Parity (HR=0.70; 95% CI: 0.63-0.78, parous vs. nulliparous), smoking status (HR=0.69; 95% CI: 0.58-0.82, current vs. never smoking) and menopausal status (HR=0.79; 95% CI: 0.73-0.87, natural menopause &amp;lt;50 years vs. natural menopause ≥ 50 years) were inversely associated with risk of DCIS overall. Whereas, positive family history of breast cancer (HR=1.46; 95% CI: 1.36-1.57), personal history of benign breast disease (BBD) (HR=1.73; 95% CI: 1.62-1.85), and current use of combination estrogen and progestin hormone replacement therapy (HR=1.15; 95% CI: 1.04-1.28) were associated with higher risk of DCIS. In analyses stratified on DCIS grade, history of BBD was more strongly associated with higher risk of low-grade (HR=2.21; 95% CI: 1.81-2.70) than with high-grade DCIS (HR=1.29; 95% CI:1.04-1.60) (p for heterogeneity=0.001). Current combination estrogen and progestin hormone replacement therapy use was associated with a higher risk of high-grade DCIS (HR=1.40; 95% CI:1.03-1.90) but not low-grade DCIS (HR=1.02; 95% CI: 0.75-1.40), but the difference by grade was not statistically significant (p=0.5). Conclusions: In this study, which is the first to comprehensively assess risk factors by DCIS grade, the association between personal history of BBD and risk of DCIS appeared to differ by grade. Due to limited power for some risk factor analyses, future studies using larger prospective cohorts or pooled data should be conducted to better identify these associations. Citation Format: Puvanesarajah S, Gapstur SM, Gansler T, Patel AV, Gaudet MM. Risk factors for high-grade and low-grade DCIS in the cancer prevention study-II nutrition cohort [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-08-07.

Micro-RNA-181a suppresses progestin-promoted breast cancer cell growth

BackgroundRecent investigations have indicated that hormone therapy may increase the risk of breast cancer (BC), and the addition of synthetic progestins may play a critical role in this. Several studies have pointed out the important role of progesterone receptor membrane component 1 (PGRMC1) in the development of BC, especially with hormone therapy using progestins. Although the deregulation of microRNA-181a (miR-181a) is often associated with human BC, the effect of miR-181a on PGRMC1 expression during hormone therapy has not been investigated. MethodsCell viability assay and apoptosis assay were performed to investigate the pro-BC effect of progestin (norethisterone, NET) and anti-BC effect of miR-181a on MCF-7 cells. Quantitative RT-PCR and Western blot analysis were used to evaluate gene expressions in the NET-treated MCF-7 cells. ResultsNET dose-dependently increased BC cell viability and this effect was accompanied by increased expression of PGRMC1. Overexpression of miR-181a strongly reduced the cell viability of MCF-7 cells, mainly through increased apoptosis, which was evidenced by substantially increased gene expression of pro-apoptosis factors such as BAX and CASPASE 9 in miR-181a overexpressed cells. Importantly, miR-181a abrogated NET-stimulated cell viability and PGRMC1 expression. ConclusionsWe provide evidence that miR-181a promotes MCF-7 cell apoptosis. Moreover, miR-181a suppressed NET-provoked cell viability and PGRMC1 expression in MCF-7 cells. These data may suggest a therapeutic strategy of using miR-181a to reduce BC risk in progestin hormone replacement therapy.

The Proliferative Response to p27 Down-Regulation in Estrogen Plus Progestin Hormonal Therapy is Lost in Breast Tumors

Increased proliferation and breast cancer risk has been observed in postmenopausal women receiving estrogen (E) + progestin hormone replacement therapy (HRT). Progestin action is mediated through two progesterone receptor (PR) isoforms, PRA and PRB, with unique transcriptional activity and function. The current study examines hormonal regulation of PR isoforms in the normal postmenopausal human breast and the mechanism by which progestins increase proliferation and breast cancer risk. Archival benign breast biopsies from postmenopausal and premenopausal women, and luminal breast tumor biopsies from postmenopausal women, were analyzed for regulation of PRA and PRB expression by E and E+medroxyprogesterone acetate (MPA). In the postmenopausal breast without HRT, PRA and PRB expression was decreased compared to the premenopausal breast. Both E (n = 12) and E+MPA (n = 13) HRT in the postmenopausal breast were associated with increased PRA and PRB expression, increased nuclear cyclin E expression, and decreased nuclear p27 expression compared to no HRT (n = 16). With E+MPA HRT, there was a further decrease in nuclear p27 and increased Receptor Activator of NF-kappa B Ligand (RANKL) expression compared to E-alone HRT. In luminal breast cancers, E+MPA HRT (n = 6) was also associated with decreased nuclear expression of the cell cycle inhibitor p27 compared to E HRT (n = 6), but was not associated with increased proliferation. These results suggest that p27 mediates progestin-induced proliferation in the normal human breast and that regulation of this proliferative response by E+MPA is lost in breast tumors.

Hormone replacement therapy use in UK general practice: Duration, discontinuation and women’s experience

Objective Investigate characteristics of women treated with combined estrogen and progestogen hormone replacement therapy (study-HRT); HRT patterns; reasons and outcomes associated with HRT discontinuation. Study design Retrospective observational study using The Health Improvement Network database examining women’s characteristics and treatment patterns (Database). Postal questionnaire exploring reasons and outcomes associated with HRT discontinuation (Survey). Main outcome measures Database: Demographic and clinical characteristics. HRT patterns, time from diagnosis to treatment, duration of treatment, type of treatment and change of treatment (switch, add-on, re-start and discontinuation). Survey: HRT therapy status, menopause rating scale and reasons for discontinuation. Results Database: 8968 women prescribed study-HRT between January 2006 and January 2010 were matched 1:1 on GP practice and age with women not prescribed HRT. Women prescribed study-HRT were more likely to be a current/past smoker ( p&lt;0.05) and experienced higher levels of co-morbidities related to menopause ( p &lt; 0.05) versus women not prescribed HRT. Treatment duration was approximately 14 months and 95% changed treatment during the study. Survey: 116 respondents. Women on HRT had lower MRS scores ( p &lt; 0.05) than women who discontinued HRT. Main reasons for discontinuation were medical advice, side-effects/potential side-effects. Fear of breast cancer was also stated as a reason. Conclusions Duration of HRT was relatively short, with 95% of women changing treatment. HRT discontinuation was associated with more severe menopause symptoms. Medical advice and concerns about side-effects were major reasons for the discontinuation, suggesting that there was a need for a balanced dialogue with women about risks and benefits of HRT, as emphasised by NICE guidance.

Abstract P1-16-06: Luteolin inhibits progestin-dependent VEGF induction, stem-cell like characteristics, and tumor progression of human breast cancer cells

Abstract Clinical trials and epidemiological evidence show that combined estrogen (E) and progestin (P) hormone replacement therapy (HRT) increases the risk of breast cancer in postmenopausal women, whereas HRT containing E alone does not. Tumor progression is dependent on angiogenesis, which provides nutrients vital to the developing cancer. We previously showed, both in vitro and in vivo, that natural and synthetic P (including the widely used progestin Medroxyprogesterone acetate, MPA), increase production of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human breast cancer cells (Cancer Res., 1998, 58:392). This effect is blocked by the anti-progestin RU-486, suggesting involvement of progesterone receptors in the process (Int J Cancer, 2001, 92:469). Evidence from our laboratory using in vivo breast cancer models suggests that P accelerates the development of tumors from latent tumorigenic cells. This leads to the formation of palpable tumors and tumor metastasis, processes that may be attributed to increased production of VEGF (Cancer Res., 2007, 67:9929; Menopause, 2010, 17:1040). RU-486 blocks P-dependent VEGF production and thereby reduces tumor growth; however, the anti-progestin has severe side-effects averting its long-term use. Recently, we have studied less toxic naturally-occurring compounds for their ability to antagonize P-dependent VEGF induction and block tumor progression. In this study, we tested the effects of luteolin, a flavonoid commonly found in fruits and vegetables, on proliferation of BT-474 and T47-D breast cancer cells and their P-dependent production of VEGF. Luteolin treatment (25-100 μM) for 24-48 h reduced in vitro tumor cell viability and induced apoptosis. Interestingly, treatment with a lower concentration of luteolin (10 μM) blocked the production of P-dependent VEGF, indicating that VEGF suppression precedes luteolin-mediated loss of cell viability. Furthermore, luteolin (20 mg/kg, i.p.) suppressed the growth of MPA-dependent T47-D human xenograft tumors in nude mice. Immunohistochemical analysis showed that luteolin reduced P-induced VEGF in tumor sections (p&amp;lt;0.05). These findings strongly suggest that the flavonoid disrupts tumor progression by blocking P-dependent angiogenesis and preventing tumor cell proliferation. Furthermore, luteolin blocked the MPA-induced acquisition of stem cell like properties by breast cancer cells; CD44 expression, ALDH activity and mammosphere formation were all reduced by the flavonoid. We contend therefore that luteolin is a compound with valuable therapeutic properties. Its ability to reduce levels of VEGF, coupled with its capacity to interfere with the acquisition of stem-cell like properties by breast cancer cells, make luteolin a compound with significant clinical potential in the battle against P-dependent human breast cancer. Supported by a COR award from the College of Veterinary Medicine and in part by funds from generous donors to the Ellis Fischel Cancer Center, University of Missouri. Citation Format: Hyder SM, Cook MT, Besch-Williford C, Liang Y. Luteolin inhibits progestin-dependent VEGF induction, stem-cell like characteristics, and tumor progression of human breast cancer cells. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-16-06.

Abstract 4159: Therapeutic effects of luteolin against progestin-dependent breast cancer involves induction of apoptosis, and suppression of both stem-cell-like cells and angiogenesis

Abstract Clinical and epidemiological evidence show that combined estrogen (E) and progestin (P) hormone replacement therapy (HRT) increases the risk of breast cancer in postmenopausal women. Tumor progression is dependent on cell survival and angiogenesis, which provides nutrients vital to the developing cancer. We have shown that physiological levels of P (10 nM), including medroxyprogesterone acetate (MPA), which is widely used in HRT, increases the production of the potently angiogenic vascular endothelial growth factor (VEGF), in human breast cancer cells both in vitro and in vivo. The anti-progestin RU-486 blocks this effect, suggesting the involvement of progesterone receptors in the process (Int J Cancer, 2001, 92:469). Evidence from our laboratory using in vivo breast cancer models suggests that P accelerates the development of tumors from latent tumorigenic cells, leading to the development of palpable tumors (Cancer Res., 2007, 67:9929; Clin Can Res, 2006, 12:4062), a process that may be attributed to increased production of VEGF. RU-486 blocks P-dependent VEGF production and thereby reduces tumor growth; however, the anti-progestin has severe side-effects and therefore cannot be used in the long-term. Recently, we have been studying less toxic naturally-occurring compounds for their ability to block P-dependent tumor progression. We tested the effects of the flavonoid luteolin, which is commonly found in fruits and vegetables, on proliferation of BT-474 and T47-D breast cancer cells and their production of VEGF. Luteolin treatment (10-100 μM) for 24 h reduced tumor cell viability, induced apoptosis, blocked P-dependent increases in CD44 high stem-cell-like cells, and blocked production of P-dependent VEGF induction in vitro. Interestingly, luteolin also reduced the ability of cells to form mammospheres, a characteristic of self-renewable cells. Furthermore, luteolin (20 mg/kg, i.p.) suppressed the growth of MPA-dependent BT-474 human xenograft tumors in nude mice. Immunohistochemical analysis showed that luteolin significantly reduced P-induced VEGF production in vitro (p&amp;lt;0.05). Our findings strongly suggest that luteolin disrupts tumor progression by blocking several processes that are vital to P-dependent tumor development. We contend therefore that luteolin is a compound with valuable therapeutic properties against P-dependent human breast cancer. Supported by a COR award from the College of Veterinary Medicine. Citation Format: Matthew Thomas Cook, Yayun Liang, Sandy Goyette, Benford Mafuvadze, Cynthia Besch-Williford, Salman Hyder. Therapeutic effects of luteolin against progestin-dependent breast cancer involves induction of apoptosis, and suppression of both stem-cell-like cells and angiogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4159. doi:10.1158/1538-7445.AM2015-4159

Influences of hormone replacement therapy on olfactory and cognitive function in postmenopausal women

Olfactory dysfunction can be an early sign of Alzheimer’s disease. Since hormone replacement therapy (HRT) may protect against Alzheimer’s disease in postmenopausal women, the question arises as to whether it also protects against olfactory dysfunction in such women. A total of three olfactory and 12 neurocognitive tests were administered to 432 healthy postmenopausal women with varied HRT histories. Serum levels of reproductive hormones were obtained for all subjects; APOE-ε4 haplotype was determined for 77 women. National Adult Reading Test and Odor Memory/Discrimination Test scores were positively influenced by HRT. Odor Identification and Odor Memory/Discrimination Test scores were lower for women who scored poorly on a delayed recall test, a surrogate for mild cognitive impairment. The Wechsler Adult Intelligence Scale, Revised, as a Neuropsychological Instrument Spatial Span Backwards Test scores were higher in women receiving estrogen and progestin HRT and directly correlated with serum testosterone levels, the latter implying a positive effect of testosterone on spatial memory. APOE-ε4 was associated with poorer odor threshold test scores. These data suggest that HRT positively influences a limited number of olfactory and cognitive measures during menopause.

Raloxifene hydrochloride treatment leads to better outcomes than medroxyprogesterone acetate when paired with estrogen in ovariectomized cholesterol-fed rabbits.

The benefits of estrogen in cardiovascular system include a reduction in low-density lipoprotein cholesterol (LDL-C), decrease in LDL oxidation, and enhancement of vascular function [1]. Estrogen replacement therapy, however, has been linked to an increased risk of tissue-specific side effects including breast cancer and uterine cancer [2]. These issues have led to the development of hormone replacement therapy (HRT) which combines estrogen and progestin. Progestin can reverse endometrial hyperplasia induced by estrogen. The most commonly used progestin in HRT is medroxyprogesterone acetate (MPA), a synthetic progestin, although there is some evidence that the administration of MPA is not as beneficial as natural progesterone [3]. Findings from randomized placebo-controlled trials have demonstrated that the combination of estrogen and MPA does not confer cardiac protection and may increase the risk of coronary heart disease among healthy postmenopausal women, especially in the first year after initiation of hormone therapy. Furthermore, an increase in the risk of breast cancer was also found with this therapy [4]. Although the role of progestin remains poorly defined, it is possible that the coadministration of progestin could counteract the cardioprotective effects of estrogen [5]. In an effort to obtain the beneficial effects and reduce the risks associated with HRT, new replacement therapy formulations including selective estrogen receptor modulators (SERMs) have been developed. However, in a preclinical trial, treatment with bazedoxifene acetate (BZA), a new third-generation SERM, and conjugated equine estrogen (CEE) in combination did not show significant effects on plasma lipid profiles, and BZA treatment had no adverse

Molecular modulation of estrogen-induced apoptosis by synthetic progestins in hormone replacement therapy: an insight into the women's health initiative study.

Hormone replacement therapy (HRT) is widely used to manage menopausal symptoms in women and can be comprised of an estrogen alone or an estrogen combined with a progestin. The Women's Health Initiative demonstrated in their randomized trials that estrogen alone HRT decreases the risk of breast cancer in postmenopausal women, whereas combined estrogen plus a progestin (medroxyprogesterone acetate, MPA) HRT increases this risk. Long-term estrogen-deprived MCF-7:5C cells were used to model the postmenopausal breast cancer cell environment. MPA is able to modify E2-induced apoptosis in MCF-7:5C cells. MPA, similar to dexamethasone, increases glucocorticoid receptor (GR) transcriptional activity, increases SGK1, a GR target gene, and can be blocked by RU486 (an antiglucocorticoid), suggesting that it functions through the GR. Norethindrone acetate (NETA), another progestin used in HRT, acts like an estrogen at high doses, upregulating estrogen receptor target genes and generating apoptosis in MCF-7:5C cells. The data suggest that women taking HRT comprising an estrogen plus MPA may have an increased risk of breast cancer due to MPA acting as a glucocorticoid and blunting E2-induced apoptosis in this environment. Therefore, perhaps other approved progestins (e.g., NETA) should be considered as alternatives to MPA.

Hormone use and risk for lung cancer: a pooled analysis from the International Lung Cancer Consortium (ILCCO)

Background:The association between oral contraceptive (OC) use, hormone replacement therapy (HRT) and lung cancer risk in women is still debated.Methods:We performed a pooled analysis of six case–control studies (1961 cases and 2609 controls) contributing to the International Lung Cancer Consortium. Potential associations were investigated with multivariable unconditional logistic regression and meta-analytic models. Multinomial logistic regressions were performed to investigate lung cancer risk across histologic types.Results:A reduced lung cancer risk was found for OC (odds ratio (OR)=0.81; 95% confidence interval (CI): 0.68–0.97) and HRT ever users (OR=0.77; 95% CI: 0.66–0.90). Both oestrogen only and oestrogen+progestin HRT were associated with decreased risk (OR=0.76; 95% CI: 0.61–0.94, and OR=0.66; 95% CI: 0.49–0.88, respectively). No dose-response relationship was observed with years of OC/HRT use. The greatest risk reduction was seen for squamous cell carcinoma (OR=0.53; 95% CI: 0.37–0.76) in OC users and in both adenocarcinoma (OR=0.79; 95% CI: 0.66–0.95) and small cell carcinoma (OR=0.37; 95% CI: 0.19–0.71) in HRT users. No interaction with smoking status or BMI was observed.Conclusion:Our findings suggest that exogenous hormones can play a protective role in lung cancer aetiology. However, given inconsistencies with epidemiological evidence from cohort studies, further and larger investigations are needed for a more comprehensive view of lung cancer development in women.

Regulation of Gene Expression by Progesterone in Cancer Cells: Effects on Cyclin D1, EGFR and VEGF

Progesterone (P4) participates in the regulation of several physiological and pathological processes in mammals through the interaction with its intracellular receptors (PR), which are ligand-dependent transcription factors.Many human cancers depend on P4 for growth and metastasis, especially cancers of reproductive tissues. In women,administration of combined estrogen and progestin hormone replacement therapy for postmenopausal symptoms increases the risk of breast cancer relative to women taking estrogens alone. P4 exerts its actions through various mechanisms classified as classical and non-classical. PR has dual functions as a nuclear transcription factor and as a modulator of cell signaling pathways. Many PR target genes do not contain canonical progesterone response elements (PRE) in their promoter regions and may thus be regulated by PR tethering to other transcription factors and/or rapid signaling,independent of direct PR DNA binding. We review the mechanisms involved in P4 effects on genes implicated in control of cell cycle, proliferation, angiogenesis and metastasis, such as cyclin D1 and epidermal growth factor receptor (EGFR)whose promoters lack PRE sequences, and vascular endothelial growth factor (VEGF) which gene contains PRE in its promoter region. The understanding of the molecular mechanisms involved in the regulation of cyclin D1, EGFR and VEGF expression by P4 will be helpful for the development of new cancer therapies.

Abstract 578: Apigenin blocks medroxyprogesterone acetate-dependent progression of BT-474 human breast tumor xenografts by inducing apoptosis

Abstract Recent clinical and epidemiological evidence suggests that hormone replacement therapy (HRT) containing both estrogen and progestin increases the risk of metastatic breast cancer in post-menopausal women compared with estrogen monotherapy or placebo treated women. The biological mechanisms behind this phenomenon remain obscure. We showed that medroxyprogesterone acetate (MPA), a commonly used progestin in HRT, increases the production of the potent angiogenic growth factor VEGF in breast cancer cells. The anti-progestin RU-486 blocks this effect, suggesting the involvement of progesterone receptors in the process (Int J Cancer, 2001, 92:469). This led to our hypothesis that progestins increase the angiogenic potential of latent tumorigenic cells in the breast, leading to development of palpable tumors. Using a xenograft model that was developed in our laboratory (Cancer Res., 2007, 67:9929), we previously showed that progestins promote the growth and development of BT-474 human xenograft tumors, as well as increasing BT-474 cell metastasis. In this study, we sought to determine whether apigenin, a low molecular weight flavonoid with known anti-carcinogenic properties, inhibits MPA-induced growth of BT-474 xenografts in nude mice. BT-474 human breast cancer cells were inoculated in immune-deficient mice that had been pre-inoculated with estradiol pellets. As was previously reported with this model, estradiol supported a short burst of tumor cell growth, which was followed by tumor regression. Implantation of MPA pellets rescued and stimulated further tumor growth. Administration of apigenin (50 mg/kg i.p.) inhibited the MPA-induced progression and development of BT-474 xenograft tumors. Immunohistochemical analysis revealed that the anti-tumor effects of apigenin occur through induction of tumor cell apoptosis, as measured using TUNEL assay, and also in part by suppression of cell proliferation (Ki67). Apigenin therefore appears to have therapeutic potential against progestin-dependent breast cancer and might be considered as a neutraceutical for treating progestin-dependent tumors in women already exposed to progestins. This study was supported by a COR award from the College of Vet Medicine, and research funds from RADIL, University of Missouri. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 578. doi:1538-7445.AM2012-578

Postmenopausal vaginal bleeding in women using hormone replacement therapy

To estimate the risk of endometrial cancer in postmenopausal women presenting with vaginal bleeding using estrogen-progestogen hormone replacement therapy (HRT) regimens and to assess if the duration of HRT use has an effect on the risk of diagnosing endometrial cancer. Cross-sectional study of consecutive women presenting with postmenopausal vaginal bleeding at a gynaecological oncology centre in the UK. Main outcome measures Endometrial cancer diagnosis. Over a 62-month period, 4847 women were investigated for postmenopausal vaginal bleeding. The majority of women (4097, 84.5%) did not use any HRT preparation at the time of initial referral and 750 (15.5%) women were using combined HRT preparations. A total of 298 (6.1%) women were diagnosed with endometrial carcinoma. Women using HRT preparations were significantly less likely to be diagnosed with endometrial cancer compared with women not using HRT (adjusted odds ratio = 0.229, 95% CI 0.116-0.452; P < 0.0001). The longer duration of HRT use did increase the risk of diagnosing endometrial cancer in women presenting with postmenopausal vaginal bleeding, but this was not statistically significant. Postmenopausal women presenting with vaginal bleeding and using combined HRT preparations have significantly lower risk of being diagnosed with endometrial cancer when compared with women not using HRT.