Browsing by Subject "ESTROGEN"

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  • Wirtz, Ralph M.; Sihto, Harri; Isola, Jorma; Heikkila, Paivi; Kellokumpu-Lehtinen, Pirkko-Liisa; Auvinen, Paivi; Turpeenniemi-Hujanen, Taina; Jyrkkio, Sirkku; Lakis, Sotiris; Schlombs, Kornelia; Laible, Mark; Weber, Stefan; Eidt, Sebastian; Sahin, Ugur; Joensuu, Heikki (2016)
    The biological subtype of breast cancer influences the selection of systemic therapy. Distinction between luminal A and B cancers depends on consistent assessment of Ki-67, but substantial intra-observer and inter-observer variability exists when immunohistochemistry (IHC) is used. We compared RT-qPCR with IHC in the assessment of Ki-67 and other standard factors used in breast cancer subtyping. RNA was extracted from archival breast tumour tissue of 769 women randomly assigned to the FinHer trial. Cancer ESR1, PGR, ERBB2 and MKI67 mRNA content was quantitated with an RT-qPCR assay. Local pathologists assessed ER, PgR and Ki-67 expression using IHC. HER2 amplification was identified with chromogenic in situ hybridization (CISH) centrally. The results were correlated with distant disease-free survival (DDFS) and overall survival (OS). qPCR-based and IHC-based assessments of ER and PgR showed good concordance. Both low tumour MKI67 mRNA (RT-qPCR) and Ki-67 protein (IHC) levels were prognostic for favourable DDFS [hazard ratio (HR) 0.42, 95 % CI 0.25-0.71, P = 0.001; and HR 0.56, 0.37-0.84, P = 0.005, respectively] and OS. In multivariable analyses, cancer MKI67 mRNA content had independent influence on DDFS (adjusted HR 0.51, 95 % CI 0.29-0.89, P = 0.019) while Ki-67 protein expression had not any influence (P = 0.266) whereas both assessments influenced independently OS. Luminal B patients treated with docetaxel-FEC had more favourable DDFS and OS than those treated with vinorelbine-FEC when the subtype was defined by RT-qPCR (for DDFS, HR 0.52, 95 % CI 0.29-0.94, P = 0.031), but not when defined using IHC. Breast cancer subtypes approximated with RT-qPCR and IHC show good concordance, but cancer MKI67 mRNA content correlated slightly better with DDFS than Ki-67 expression. The findings based on MKI67 mRNA content suggest that patients with luminal B cancer benefit more from docetaxel-FEC than from vinorelbine-FEC.
  • Sievanen, Tero; Tormakangas, Timo; Laakkonen, Eija K.; Mecklin, Jukka-Pekka; Pylvänäinen, Kirsi; Seppälä, Toni T.; Peltomäki, Paivi; Sipila, Sarianna; Sillanpää, Elina (2021)
    Simple Summary Lifestyle modifies cancer risk in the general public. How lifestyle modifies cancer risk in individuals carrying the inherited pathogenic gene variants in DNA mismatch repair genes (Lynch syndrome) remains understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, physical activity, and cancer risk among Finnish Lynch syndrome carriers (n = 465, 54% women). The results of our study indicated that longitudinal weight gain increases cancer risk, whereas being highly physically active during adulthood could decrease cancer risk in men. Further, women were observed to be less prone to lifestyle-related risk factors than men. The results emphasize the role of weight maintenance and high-intensity physical activity throughout the lifespan, especially in men with Lynch syndrome. Lynch syndrome (LS) increases cancer risk. There is considerable individual variation in LS cancer occurrence, which may be moderated by lifestyle factors, such as body weight and physical activity (PA). The potential associations of lifestyle and cancer risk in LS are understudied. We conducted a retrospective study with cancer register data to investigate associations between body weight, PA, and cancer risk among Finnish LS carriers. The participants (n = 465, 54% women) self-reported their adulthood body weight and PA at 10-year intervals. Overall cancer risk and colorectal cancer (CRC) risk was analyzed separately for men and women with respect to longitudinal and near-term changes in body weight and PA using extended Cox regression models. The longitudinal weight change was associated with an increased risk of all cancers (HR 1.02, 95% CI 1.00-1.04) and CRC (HR 1.03, 1.01-1.05) in men. The near-term weight change was associated with a lower CRC risk in women (HR 0.96, 0.92-0.99). Furthermore, 77.6% of the participants retained their PA category over time. Men in the high-activity group had a reduced longitudinal cancer risk of 63% (HR 0.37, 0.15-0.98) compared to men in the low-activity group. PA in adulthood was not associated with cancer risk among women. These results emphasize the role of weight maintenance and high-intensity PA throughout the lifespan in cancer prevention, particularly in men with LS.
  • Skledar, Darja Gramec; Trontelj, Jurij; Troberg, Johanna; Tomašič, Tihomir; Zega, Anamarija; Finel, Moshe; Mašič, Lucija Peterlin (2019)
    Bisphenol AF (BPAF) is in the body mainly metabolized to the corresponding bisphenol AF glucuronide (BPAF-G). While BPAF-G is not commercially available, enzyme-assisted synthesis of BPAF-G using the human recombinant enzyme UGT2A1, purification of BPAF-G by solid phase extraction and semi-preparative HPLC and chemical characterization of BPAF-G by NMR and LC-MS/MS were performed and are described here. Furthermore, BPAF glucuronidation kinetics with the UGT enzymes that showed the highest glucuronidation activity in previous studies (i.e hepatic UGTs 1A3, 2B7, and 2B17, intestinal UGT 1A10 and UGT 2A1 that is present in airways) was performed and data is presented. Hepatic enzymes exhibited high affinities toward BPAF, while extrahepatic UGTs 2A1 and 1A10 showed the high v(max), values (3.3 and 3.0 nmol/min/mg, respectively). To understand molecular interactions of BPA, BPAF and BPAF-G with ligand biding sites of several nuclear receptors, molecular modeling was performed and data on the binding modes of BPAF, BPA, and BPAF-G in the ligand-binding sites of nuclear receptors are presented. This article is related to "Endocrine activities and adipogenic effects of bisphenol AF and its main metabolite" (Skledar et al., 2019). (C) 2018 The Authors. Published by Elsevier Inc.
  • Tuomikoski, Pauliina; Salomaa, Veikko; Havulinna, Aki; Airaksinen, Juhani; Ketonen, Matti; Koukkunen, Heli; Ukkola, Olavi; Kesaniemi, Y. Antero; Lyytinen, Heli; Ylikorkala, Olavi; Mikkola, Tomi S. (2016)
    Objectives: The role of postmenopausal hormone therapy (HT) in the incidence of acute coronary syndrome (ACS) has been studied extensively, but less is known of the impact of HT on the mortality risk due to an ACS. Study design and main outcome measures: We extracted from a population-based ACS register, FINAMI, 7258 postmenopausal women with the first ACS. These data were combined with HT use data from the National Drug Reimbursement Register; 625 patients (9%) had used various HT regimens. The death risks due to ACS before admission to hospital, 2-28, or 29-365 days after the incident ACS were compared between HT users and non-users with logistic regression analyses. Results: In all follow-up time points, the ACS death risks in HT ever-users were smaller compared to non-users. Of women with FIT ever use, 42% died within one year as compared with 52% of non-users (OR 0.62, p <0.001). Most deaths (84%) occurred within 28 days after the ACS, and in this group 36% of women with ever use of FIT (OR 0.73, p = 0.002) and 30% of women with >= 5 year FIT use (OR 0.54, p <0.001) died as compared to 43% of the non-users. Age 60 years at the HT initiation was accompanied with similar reductions in ACS mortality risk. Conclusions: Postmenopausal HT use is accompanied with reduced mortality risk after primary ACS. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
  • Olivieri, Fabiola; Ahtiainen, Maarit; Lazzarini, Raffaella; Pollanen, Eija; Capri, Miriam; Lorenzi, Maria; Fulgenzi, Gianluca; Albertini, Maria C.; Salvioli, Stefano; Alen, Markku J.; Kujala, Urho M.; Borghetti, Giulia; Babini, Lucia; Kaprio, Jaakko; Sipila, Sarianna; Franceschi, Claudio; Kovanen, Vuokko; Procopio, Antonio D. (2014)
    MiRNAs are fine-tuning modifiers of skeletal muscle regulation, but knowledge of their hormonal control is lacking. We used a co-twin case-control study design, that is, monozygotic postmenopausal twin pairs discordant for estrogen-based hormone replacement therapy (HRT) to explore estrogen-dependent skeletal muscle regulation via miRNAs. MiRNA profiles were determined from vastus lateralis muscle of nine healthy 54-62-years-old monozygotic female twin pairs discordant for HRT (median 7 years). MCF-7 cells, human myoblast cultures and mouse muscle experiments were used to confirm estrogen's causal role on the expression of specific miRNAs, their target mRNAs and proteins and finally the activation of related signaling pathway. Of the 230 miRNAs expressed at detectable levels in muscle samples, qPCR confirmed significantly lower miR-182, miR-223 and miR-142-3p expressions in HRT using than in their nonusing co-twins. Insulin/IGF-1 signaling emerged one common pathway targeted by these miRNAs. IGF-1R and FOXO3A mRNA and protein were more abundantly expressed in muscle samples of HRT users than nonusers. In vitro assays confirmed effective targeting of miR-182 and miR-223 on IGF-1R and FOXO3A mRNA as well as a dose-dependent miR-182 and miR-223 down-regulations concomitantly with up-regulation of FOXO3A and IGF-1R expression. Novel finding is the postmenopausal HRT-reduced miRs-182, miR-223 and miR-142-3p expression in female skeletal muscle. The observed miRNA-mediated enhancement of the target genes' IGF-1R and FOXO3A expression as well as the activation of insulin/IGF-1 pathway signaling via phosphorylation of AKT and mTOR is an important mechanism for positive estrogen impact on skeletal muscle of postmenopausal women.
  • Rahkola-Soisalo, Päivi; Savolainen-Peltonen, Hanna; Mika, Gissler; Hoti, Fabian; Vattulainen, Pia; Ylikorkala, Olavi; Mikkola, Tomi S. (2019)
    Introduction and hypothesisThe impact of estradiol-based hormone therapy (HT) on the incidence of stress urinary incontinence (SUI) is unknown. Therefore, we compared the use of such HT regimens and tibolone in women with and without SUI.MethodsThe women with a history of SUI operation (N=15,002) were identified from the Finnish National Hospital Discharge Register, and the control women without such an operation (N=44,389) from the Finnish Central Population Register. The use of HT was traced from the National Drug Reimbursement Register, and the odd ratios (ORs) with 95% confidence intervals (95% CIs) for SUI were calculated by using the conditional logistic regression analysis.ResultsThe cases had used any HT more often than the controls. The use of systemic estradiol-only or estradiol-progestin therapy was accompanied by an increased SUI risk (OR 3.8, 95% CI: 3.6-4.0 and OR 2.7, 95% CI: 2.6-2.9 respectively). The use of estradiol with noretisterone acetate showed a higher risk of increase than that with medroxyprogesterone acetate. Age over 55years at the initiation of systemic HT was accompanied by a higher SUI risk increase than that under 55years of age. The use of tibolone, an estradiol + levonorgestrel-releasing intrauterine device, or vaginal estradiol also increased the risk.ConclusionsThe use of HT regimens may predispose to the de novo development or worsening of pre-existing SUI. Thus, caution is needed when these regimens are prescribed to women with mild stress-related urine leakage or with established SUI risk factors.
  • Pollanen, Eija; Kangas, Reeta; Horttanainen, Mia; Niskala, Paula; Kaprio, Jaakko; Butler-Browne, Gillian; Mouly, Vincent; Sipila, Sarianna; Kovanen, Vuokko (2015)
  • Ogba, Ndiya; Manning, Nicole G.; Bliesner, Brian S.; Ambler, S. Kelly; Haughian, James M.; Pinto, Mauricio P.; Jedlicka, Paul; Joensuu, Kristiina; Heikkila, Paivi; Horwitz, Kathryn B. (2014)
  • MRI-GENIE & GISCOME Investigators; Int Stroke Genetics Consortium; Bonkhoff, Anna K.; Schirmer, Markus D.; Strbian, Daniel; Tatlisumak, Turgut; McArdle, Patrick F. (2021)
    Acute ischemic stroke affects men and women differently. In particular, women are often reported to experience higher acute stroke severity than men. We derived a low-dimensional representation of anatomical stroke lesions and designed a Bayesian hierarchical modeling framework tailored to estimate possible sex differences in lesion patterns linked to acute stroke severity (National Institute of Health Stroke Scale). This framework was developed in 555 patients (38% female). Findings were validated in an independent cohort (n=503, 41% female). Here, we show brain lesions in regions subserving motor and language functions help explain stroke severity in both men and women, however more widespread lesion patterns are relevant in female patients. Higher stroke severity in women, but not men, is associated with left hemisphere lesions in the vicinity of the posterior circulation. Our results suggest there are sex-specific functional cerebral asymmetries that may be important for future investigations of sex-stratified approaches to management of acute ischemic stroke. Acute ischemic stroke impacts men and women differently. Here, the authors show how different lesion patterns in men and women are linked to the extent of stroke severity.
  • Vihma, Veera; Tikkanen, Matti J.; Hämäläinen, Esa (2016)
  • Raj, Rahul; Kaprio, Jaakko; Korja, Miikka; Mikkonen, Era D.; Jousilahti, Pekka; Siironen, Jari (2017)
    Background Previous epidemiological studies suggest that working-aged persons with a history of moderate-to-severe traumatic brain injury (TBI) may have an increased risk for developing neurodegenerative disease (NDD) while persons with a history of mild TBI do not. In this comprehensive nationwide study in Finland, we assessed the risk of NDD and history of moderate-to-severe TBI in the working-age population. Methods and findings We performed a population-based follow-up study using the Finnish Care Register for Health Care to identify all persons between the ages of 18 and 65 years hospitalized during 1987-2014 due to TBI who did not have a baseline NDD diagnosis. We compared the risk of hospitalization with NDD between persons hospitalized due to moderate-to-severe TBI (intracranial lesions) and persons hospitalized due to mild TBI (no intracranial lesions). Follow-up NDD diagnoses were recorded from 1 year following the TBI to the end of 2014. NDD diagnoses included dementia, Parkinson disease, and amyotrophic lateral sclerosis. We used a Cox proportional hazards model, adjusting for age, sex, education, and socioeconomic group, to assess the association between TBI and NDD. In total, 19,936 and 20,703 persons with a history of moderate-to-severe TBI and mild TBI, respectively, were included. The overall time at risk was 453,079 person-years (median 10 years per person). In total, 3.5% (N = 696) persons in the moderate-to-severe TBI group developed NDD compared to 1.6% (N = 326) in the mild TBI group. After adjusting for covariates, moderate-to-severe TBI was associated with an increased risk for NDD, with a hazard ratio (HR) of 1.8 (95% CI 1.6-2.1) compared to mild TBI. Of the NDD subtypes, only moderate-to-severe TBI was associated with an increased risk for dementia (HR 1.9, 95% CI 1.6-2.2). Yet, this large-scale epidemiological study does not prove that there is a causal relationship between moderate-to-severe TBI and NDD. Further, the Care Register for Health Care includes only hospitalized persons; thus, patients diagnosed with NDD in the outpatient setting may have been missed. Additional limitations include the potential for miscoding and unmeasured confounds. Conclusions In working-aged persons, a history of moderate-to-severe TBI is associated with an increased risk for future dementia but not for Parkinson disease or amyotrophic lateral sclerosis.
  • Dominguez-Valentin, Mev; Seppälä, Toni T.; Engel, Christoph; Aretz, Stefan; Macrae, Finlay; Winship, Ingrid; Capella, Gabriel; Thomas, Huw; Hovig, Eivind; Nielsen, Maartje; Sijmons, Rolf H.; Bertario, Lucio; Bonanni, Bernardo; Tibiletti, Maria Grazia; Cavestro, Giulia Martina; Mints, Miriam; Gluck, Nathan; Katz, Lior; Heinimann, Karl; Vaccaro, Carlos A.; Green, Kate; Lalloo, Fiona; Hill, James; Schmiegel, Wolff; Vangala, Deepak; Perne, Claudia; Strauss, Hans-Georg; Tecklenburg, Johanna; Holinski-Feder, Elke; Steinke-Lange, Verena; Mecklin, Jukka-Pekka; Plazzer, John-Paul; Pineda, Marta; Navarro, Matilde; Vidal, Joan Brunet; Kariv, Revital; Rosner, Guy; Alejandra Pinero, Tamara; Laura Gonzalez, Maria; Kalfayan, Pablo; Sampson, Julian R.; Ryan, Neil A. J.; Evans, D. Gareth; Moller, Pal; Crosbie, Emma J. (2020)
    Purpose: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. Methods: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. Results: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (similar to 90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). Conclusions: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.
  • Leppänen, Jonna; Randell, Kaisa; Schwab, Ursula; Pihlajamäki, Jussi; Keski-Nisula, Leea; Laitinen, Tomi; Heinonen, Seppo (2020)
    Background This study was made to figure out, does low and high estradiol levels during in vitro fertilization (IVF) cycles have a different effect on carotid artery distensibility (Cdis), carotid artery diameter (Cdia), blood pressure and metabolic factors? Can the stimulation protocol be considered safe to women's vasculature? Methods We studied 28 women having a long agonist protocol IVF-treatment in Kuopio University Hospital during the years 2011-2016. Patients were examined at three time points: in the beginning of their own period (low estradiol), during the gonadotrophin releasing hormone (GnRH) analogue downregulation (low estradiol) and during the follicle stimulating hormone (FSH) stimulation (high estradiol). Women served as their own controls and their menstrual phase (2- to 5-day period after the beginning of menstruation with low estrogen) was used as the reference. Cdis and Cdia were assessed using ultrasound. Blood pressure, weight, estradiol levels and lipids were monitored. Results Cdis, Cdia, systolic and diastolic blood pressures peaked during the GnRH-analogue treatment with the lowest estradiol levels. Cdis, Cdia and systolic blood pressures declined by 11% (P = 0.002), 3,8% (P <0.001) and 2,5% (P = 0.026) during the FSH-stimulation when the estradiol levels were high. Cdis correlated significantly (P <0.05) with systolic blood pressure, diastolic blood pressure and triglycerides in high estrogenic environment and with diastolic blood pressure (P <0.05) when estrogen profiles were low. Conclusions Carotid artery stiffens during the high estradiol levels compared to low levels and this was not explained by the higher diameter of the carotid artery, hyperlipidemia or blood pressure profiles. All the changes in Cdis and Cdia are variations of normal, and if there is no history of cardiovascular problems, it can be considered, that the stimulation protocol is not hazardous to vasculature.
  • Savolainen-Peltonen, Hanna; Rahkola-Soisalo, Päivi; Hoti, Fabian; Vattulainen, Pia; Gissler, Mika; Ylikorkala, Olavi; Mikkola, Tomi S. (2019)
    OBJECTIVES To compare the use of hormone therapy between Finnish postmenopausal women with and without a diagnosis for Alzheimer's disease. DESIGN Nationwide case-control study. SETTING Finnish national population and drug register, between 1999 and 2013. PARTICIPANTS All postmenopausal women (n= 84 739) in Finland who, between 1999 and 2013, received a diagnosis of Alzheimer's disease from a neurologist or geriatrician, and who were identified from a national drug register. Control women without a diagnosis (n= 84 739), matched by age and hospital district, were traced from the Finnish national population register. INTERVENTIONS Data on hormone therapy use were obtained from the Finnish national drug reimbursement register. MAIN OUTCOME MEASURES Odds ratios and 95% confidence intervals for Alzheimer's disease, calculated with conditional logistic regression analysis. RESULTS In 83 688 (98.8%) women, a diagnosis for Alzheimer's disease was made at the age of 60 years or older, and 47 239 (55.7%) women had been over 80 years of age at diagnosis. Use of systemic hormone therapy was associated with a 9-17% increased risk of Alzheimer's disease. The risk of the disease did not differ significantly between users of estradiol only (odds ratio 1.09, 95% confidence interval 1.05 to 1.14) and those of oestrogen-progestogen (1.17, 1.13 to 1.21). The risk increases in users of oestrogen-progestogen therapy were not related to different progestogens (noreth isterone acetate, medroxyprogesterone acetate, or other progestogens); but in women younger than 60 at hormone therapy initiation, these risk increases were associated with hormone therapy exposure over 10 years. Furthermore, the age at initiation of systemic hormone therapy was not a decisive determinant for the increase in risk of Alzheimer's disease. The exclusive use of vaginal estradiol did not affect the risk of the disease (0.99, 0.96 to 1.01). CONCLUSIONS Long term use of systemic hormone therapy might be accompanied with an overall increased risk of Alzheimer's disease, which is not related to the type of progestogen or the age at initiation of systemic hormone therapy. By contrast, use of vaginal estradiol shows no such risk. Even though the absolute risk increase for Alzheimer's disease is small, our data should be implemented into information for present and future users of hormone therapy.
  • Kim, Minah; Park, Hyeung Ju; Seol, Jae Won; Jang, Jeon Yeob; Cho, Young-Suk; Kim, Kyu Rae; Choi, Youngsok; Lydon, John P.; DeMayo, Francesco J.; Shibuya, Masabumi; Ferrara, Napoleone; Sung, Hoon-Ki; Nagy, Andras; Alitalo, Kari; Koh, Gou Young (2013)