Browsing by Subject "METFORMIN"

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  • Acosta, Tania; Barengo, Noel C.; Arrieta, Astrid; Ricaurte, Carlos; Tuomilehto, Jaakko O. (2018)
    Type 2 diabetes (T2D) imposes a heavy public health burden in both developed and developing countries. It is necessary to understand the effect of T2D in different settings and population groups. This report aimed to present baseline characteristics of study participants in the demonstration area for the Type 2 Diabetes Prevention in Barranquilla and Juan Mina (DEMOJUAN) project after randomization and to compare their fasting and 2-hour glucose levels according to lifestyle and T2D risk factor levels. The DEMOJUAN project is a randomized controlled field trial. Study participants were recruited from study sites using population-wide screening using the Finnish Diabetes Risk Score (FINDRISC) questionnaire. All volunteers with FINDRISC of >= 13 points were invited to undergo an oral glucose tolerance test (OGTT). Participant inclusion criteria for the upcoming field trial were either FINDRISC of >= 13 points and 2-hour post-challenge glucose level of 7.0 to 11.0mmol/L or FINDRISC of >= 13 points and fasting plasma glucose level of 6.1 to 6.9mmol/L. Lifestyle habits and risk factors for T2D were assessed by trained interviewers using a validated questionnaire. Among the 14,193 participants who completed the FINDRISC questionnaire, 35% (n=4915) had a FINDRISC score of >= 13 points and 47% (n=2306) agreed to undergo the OGTT. Approximately, 33% (n=772) of participants underwent the OGTT and met the entry criteria; these participants were randomized into 3 groups. There were no statistically significant differences found in anthropometric or lifestyle risk factors, distribution of the glucose metabolism categories, or other diabetes risk factors between the 3 groups (P>.05). Women with a past history of hyperglycaemia had significantly higher fasting glucose levels than those without previous hyperglycaemia (103 vs 99mg/dL; P Lifestyle habits and risk factors were evenly distributed among the 3 study groups. No differences were found in fasting or 2-hour glucose levels among different lifestyle or risk factor categories with the exception of body mass index, past history of hyperglycaemia, and age of 64 years in women.
  • Hosio, Mayu; Urpilainen, Elina; Hautakoski, Ari; Marttila, Mikko; Arffman, Martti; Sund, Reijo; Ahtikoski, Anne; Puistola, Ulla; Läärä, Esa; Karihtala, Peeter; Jukkola, Arja (2021)
    We investigated the survival of female patients with pre-existing type 2 diabetes (T2D) diagnosed with invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) of breast, in relation to the use of metformin, other antidiabetic medication (ADM) and statins. The study cohort consisted of 3,165 women (2,604 with IDC and 561 with ILC). The cumulative mortality from breast cancer (BC) and from other causes was calculated using the Aalen-Johansen estimator. The cause-specific mortality rates were analysed by Cox models, and adjusted hazard ratios (HRs) were estimated for the use of different medications. No evidence of an association of metformin use with BC mortality was observed in either IDC (HR 0.92, 95% confidence interval [CI] 0.64-1.31) or ILC (HR 0.68, 95% CI 0.32-1.46) patients, when compared to other oral ADMs. The mortality from other causes was found to be lower amongst the IDC patients using metformin (HR 0.64, 95% CI 0.45-0.89), but amongst ILC patients the evidence was inconclusive (HR 1.22, 95% CI 0.64-2.32). Statin use was consistently associated with reduced mortality from BC in IDC patients (HR 0.77, 95% CI 0.62-0.96) and ILC patients (HR 0.59, 95% CI 0.37-0.96), and also mortality from other causes in IDC patients (HR 0.81, 95% CI 0.67-0.96) and in ILC patients (HR 0.66, 95% CI 0.43-1.01). We found no sufficient evidence for the possible effects of metformin and statins on the prognosis of BC being different in the two histological subtypes.
  • Latorre, Jèssica; Ortega, Francisco J.; Liñares-Pose, Laura; Moreno-Navarrete, José M.; Lluch, Aina; Comas, Ferran; Oliveras-Cañellas, Núria; Ricart, Wifredo; Höring, Marcus; Zhou, You; Liebisch, Gerhard; Nidhina Haridas, P.A.; Olkkonen, Vesa M.; López, Miguel; Fernández-Real, José M. (2020)
    Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled b-oxidation, redirecting FA metabolism fromenergy storage to expenditure. Interpretation: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associacio Catalana de Diabetis (ACD), Sociedad Espanola de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economia y Competitividad (MINECO), "La Caixa" Foundation, and CIBER de la Fisiopatologia de la Obesidad y Nutricion (CIBEROBN). (c) 2020 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license. (
  • Bakula, Daniela; Ablasser, Andrea; Aguzzi, Adriano; Antebi, Adam; Barzilai, Nir; Bittner, Martin-Immanuel; Jensen, Martin Borch; Calkhoven, Cornelis F.; Chen, Danica; de Grey, Aubrey D. N. J.; Feige, Jerome N.; Georgievskaya, Anastasia; Gladyshev, Vadim N.; Golato, Tyler; Gudkov, Andrei V.; Hoppe, Thorsten; Kaeberlein, Matt; Katajisto, Pekka; Kennedy, Brian K.; Lal, Unmesh; Martin-Villalba, Ana; Moskalev, Alexey A.; Ozerov, Ivan; Petr, Michael A.; Reason, Matthew; Rubinsztein, David C.; Tyshkovskiy, Alexander; Vanhaelen, Quentin; Zhavoronkov, Alex; Scheibye-Knudsen, Morten (2019)
    An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland ( This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.
  • Matikainen, Niina; Söderlund, Sanni; Björnson, Elias; Pietiläinen, Kirsi; Hakkarainen, Antti; Lundbom, Nina; Taskinen, Marja-Riitta; Boren, Jan (2019)
    Aims Patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) exhibit considerable residual risk for cardiovascular disease (CVD). There is, therefore, increasing interest in targeting postprandial lipid metabolism and remnant cholesterol. Treatment with the glucagon-like peptide 1 (GLP-1) analogue liraglutide reduces CVD risk by mechanisms that remain unexplained in part. Here we investigated the effects of liraglutide intervention on ectopic fat depots, hepatic lipogenesis and fat oxidation, postprandial lipid metabolism and glycaemia in humans with type 2 diabetes. Methods The effect of liraglutide was investigated in 22 patients with adequately controlled type 2 diabetes. Patients were randomly allocated, in a single-blind fashion, to either liraglutide 1.8 mg or placebo once daily for 16 weeks. Because liraglutide is known to promote weight loss, the study included dietary counselling to achieve similar weight loss in the liraglutide and placebo groups. Cardiometabolic responses to a high-fat mixed meal were measured before and at the end of the liraglutide intervention. Results Weight loss at Week 16 was similar between the groups: -2.4 kg (-2.5%) in the liraglutide group and -2.1 kg (-2.2%) in the placebo group. HBA1c improved by 6.4 mmol/mol (0.6%) in the liraglutide group (P = 0.005). Liver fat decreased in both groups, by 31% in the liraglutide group and by 18% in the placebo group, but there were no significant changes in the rate of hepatic de novo lipogenesis or beta-hydroxybutyrate levels, a marker of fat oxidation. We observed significant postprandial decreases in triglycerides only in plasma, chylomicrons and VLDL, and remnant particle cholesterol after treatment in the liraglutide group. Fasting and postprandial apoCIII concentrations decreased after liraglutide intervention and these changes were closely related to reduced glycaemia. In relative importance analysis, approximately half of the changes in postprandial lipids were explained by reductions in apoCIII concentrations, whereas less than 10% of the variation in postprandial lipids was explained by reductions in weight, glycaemic control, liver fat or postprandial insulin responses. Conclusions Intervention with liraglutide for 16 weeks produces multiple improvements in cardiometabolic risk factors that were not seen in the placebo group, despite similar weight loss. Of particular importance was a marked reduction in postprandial atherogenic remnant particles. The underlying mechanism may be improved glycaemic control, which leads to reduced expression of apoCIII, a key regulator of hypertriglyceridaemia in hyperglycaemic patients.
  • Rintamäki, Reeta; Rautio, Nina; Peltonen, Markku; Jokelainen, Jari; Keinänen-Kiukaanniemi, Sirkka; Oksa, Heikki; Saaristo, Timo; Puolijoki, Hannu; Saltevo, Juha; Tuomilehto, Jaakko; Uusitupa, Matti; Moilanen, Leena (2021)
    Aims: The Finnish National Diabetes Prevention Program (FIN-D2D) was the first large-scale diabetes prevention program in a primary health care setting in the world. The risk reduction of type 2 diabetes was 69% after one-year intervention in high-risk individuals who were able to lose 5% of their weight. We investigated long-term effects of one-year weight change on the incidence of type 2 diabetes, cardiovascular events, and all-cause mortality. Methods: A total of 10,149 high-risk individuals for type 2 diabetes were identified in primary health care centers and they were offered lifestyle intervention to prevent diabetes. Of these individuals who participated in the baseline screening, 8353 had an oral glucose tolerance test (OGTT). Complete followup data during one-year intervention were available for 2730 individuals and those were included in the follow-up analysis. The long-term outcome events were collected from national health registers after the median follow-up of 7.4 years. Results: Among individuals who lost weight 2.5 & minus;4.9% and 5% or more during the first year, the hazard ratio for the incidence of drug-treated diabetes was 0.63 (95% CI 0.49 & minus;0.81, p = 0.0001), and 0.71 (95% CI 0.56 & minus;0.90, p = 0.004), respectively, compared with those with stable weight. There were no significant differences in cardiovascular events or all-cause mortality among study participants according to oneyear weight changes. Conclusions: High-risk individuals for type 2 diabetes who achieved a moderate weight loss by one-year lifestyle counseling in primary health care had a long-term reduction in the incidence of drug-treated type 2 diabetes. The observed moderate weight loss was not associated with a reduction in cardiovascular events. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Primary Care Diabetes Europe. This is an open access article under the CC BY-NC-ND license (
  • Khatun, Masuma; Urpilainen, Elina; Ahtikoski, Anne; Arffman, Riikka K.; Pasanen, Annukka; Puistola, Ulla; Tapanainen, Juha S.; Andersson, Leif C.; Butzow, Ralf; Loukovaara, Mikko; Piltonen, Terhi T. (2021)
    Stanniocalcin-1 (STC-1) is a glycoprotein hormone involved in diverse biological processes, including regulation of calcium phosphate homeostasis, cell proliferation, apoptosis, inflammation, oxidative stress responses, and cancer development. The role of STC-1 in endometrial cancer (EC) is yet to be elucidated. In this study, we investigated the protein expression pattern of STC-1 in a tissue microarray (TMA) cohort of hysterectomy specimens from 832 patients with EC. We then evaluated the prognostic value of STC-1 expression regarding the clinicopathologic features and patients survival over a period of 140 months. Our results revealed that in EC tissue samples, STC-1 is mainly localized in the endometrial epithelium, although some expression was also observed in the stroma. Decreased STC-1 expression was associated with factors relating to a worse prognosis, such as grade 3 endometrioid tumors (p = 0.030), deep myometrial invasion (p = 0.003), lymphovascular space invasion (p = 0.050), and large tumor size (p = 0.001). Moreover, STC-1 expression was decreased in tumors obtained from obese women (p = 0.014) and in women with diabetes mellitus type 2 (DMT2; p = 0.001). Interestingly, the data also showed an association between DNA mismatch repair (MMR) deficiency and weak STC-1 expression, specifically in the endometrial epithelium (p = 0.048). No association was observed between STC-1 expression and disease-specific survival. As STC-1 expression was particularly low in cases with obesity and DMT2 in the TMA cohort, we also evaluated the correlation between metformin use and STC-1 expression in an additional EC cohort that only included women with DMT2 (n = 111). The analysis showed no difference in STC-1 expression in either the epithelium or the stroma in women undergoing metformin therapy compared to metformin non-users. Overall, our data may suggest a favorable role for STC-1 in EC behavior; however, further studies are required to elucidate the detailed mechanism and possible applications to cancer treatment.
  • Seppälä, Laura K.; Vettenranta, Kim; Pitkäniemi, Janne; Hirvonen, Elli; Leinonen, Maarit K.; Madanat-Harjuoja, Laura-Maria (2020)
    An association between maternal diabetes, its medication and childhood cancer has not been previously explored in a registry-based setting. With a case-control design, we aimed to explore whether maternal diabetes is associated with an increased risk of childhood cancer in the offspring. Combining data from population-based registries, we analyzed a total of 2,029 cases, i.e. persons with childhood cancer diagnosed under the age of 20?years between years 1996-2014 and a total of 10,103 matched population controls. The mothers of the cases/controls and their diagnoses of diabetes (DM) before/during pregnancy as well as their insulin/metformin prescriptions during pregnancy were identified. Conditional logistic regression modelling was used to analyze the risk of childhood cancer. The OR for childhood cancer among those exposed to any maternal diabetes was 1.32 (95% CI 1.14-1.54) compared to the offspring of the non-diabetic mothers. The effect of maternal diabetes on the risk of childhood cancer remained elevated even after adjusting for maternal age, parity and smoking. Our data suggest that maternal diabetes medication may reduce the risk for childhood cancer (adjusted OR 0.83, 95% CI 0.36-1.94), especially in gestational diabetes (adjusted OR 0.26, 95% CI 0.05-1.25), compared to the diabetic mothers without medication. The risk of childhood leukemia was significantly higher among children exposed to any maternal diabetes (OR 1.36, CI 1.04-1.77) compared to the unexposed. Maternal diabetes appears to be associated with an increased risk of childhood cancer in the offspring. The possible risk-reducing effect of an exposure to diabetes medication on offspring cancer risk warrants further investigation. This article is protected by copyright. All rights reserved.
  • Berg, Mika Erik Anthon; Naams, Jette-Britt; Hautala, Laura; Tolvanen, Tuomas; Ahonen, Jari; Lehtonen, Sanna; Wähälä, Kristiina (2020)
    A series of substituted sulfonanilide analogs were prepared and evaluated as novel potent inhibitors of SH2 domaincontaining inositol polyphosphate 5′-phosphatase 2 (SHIP2). SHIP2 has been shown to be a new attractive target for the treatment of insulin resistance in type 2 diabetes mellitus (T2D), which can lead to life-threatening diabetic kidney disease (DKD). Amongst the synthesized compounds, the two most promising candidates, 10 and 11, inhibited SHIP2 significantly. Additionally, these compounds induced Akt activation in a dose-dependent manner, increased the presence of glucose transporter 4 at the plasma membrane, and enhanced glucose uptake in cultured myotubes in vitro at lower concentrations than metformin, the most widely used antidiabetic drug. These results show that the novel SHIP2 inhibitors have insulin sensitizing capacity and provide prototypes for further drug development for T2D and DKD.
  • Haikala, Heidi M.; Anttila, Johanna M.; Marques, Elsa; Raatikainen, Tiina; Ilander, Mette; Hakanen, Henna; Ala-Hongisto, Hanna; Savelius, Mariel; Balboa, Diego; Von Eyss, Bjoern; Eskelinen, Vilja; Munne, Pauliina; Nieminen, Anni I.; Otonkoski, Timo; Schüler, Julia; Laajala, Teemu D.; Aittokallio, Tero; Sihto, Harri; Mattson, Johanna; Heikkilä, Päivi; Leidenius, Marjut; Joensuu, Heikki; Mustjoki, Satu; Kovanen, Panu; Eilers, Martin; Leverson, Joel D.; Klefström, Juha (2019)
    Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-X-L inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-X-L co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.
  • Zhang, Enming; Al-Amily, Israa Mohammed; Mohammed, Sarheed; Luan, Cheng; Asplund, Olof; Ahmed, Meftun; Ye, Yingying; Ben-Hail, Danya; Soni, Arvind; Vishnu, Neelanjan; Bompada, Pradeep; De Marinis, Yang; Groop, Leif; Shoshan-Barmatz, Varda; Renstrom, Erik; Wollheim, Claes B.; Salehi, Albert (2019)
    Type 2 diabetes (T2D) develops after years of prediabetes during which high glucose (glucotoxicity) impairs insulin secretion. We report that the ATP-conducting mitochondrial outer membrane voltage-dependent anion channel-1 (VDAC1) is upregulated in islets from T2D and non-diabetic organ donors under glucotoxic conditions. This is caused by a glucotoxicity-induced transcriptional program, triggered during years of prediabetes with suboptimal blood glucose control. Metformin counteracts VDAC1 induction. VDAC1 overexpression causes its mistargeting to the plasma membrane of the insulinsecreting beta cells with loss of the crucial metabolic coupling factor ATP. VDAC1 antibodies and inhibitors prevent ATP loss. Through direct inhibition of VDAC1 conductance, metformin, like specific VDAC1 inhibitors and antibodies, restores the impaired generation of ATP and glucose-stimulated insulin secretion in T2D islets. Treatment of db/db mice with VDAC1 inhibitor prevents hyperglycemia, and maintains normal glucose tolerance and physiological regulation of insulin secretion. Thus, beta cell function is preserved by targeting the novel diabetes executer protein VDAC1.
  • Yan, Yan; Ollila, Saara; Wong, Iris P. L.; Vallenius, Tea; Palvimo, Jorma J.; Vaahtomeri, Kari; Mäkelä, Tomi (2015)
    AMP-activated protein kinase (AMPK) inhibits several anabolic pathways such as fatty acid and protein synthesis, and identification of AMPK substrate specificity would be useful to understand its role in particular cellular processes and develop strategies to modulate AMPK activity in a substrate-specific manner. Here we show that SUMOylation of Z attenuates AMPK activation specifically towards mTORC1 signalling. SUMOylation is also important for rapid inactivation of AMPK, to allow prompt restoration of mTORC1 signalling. PIAS4 and its SUMO E3 ligase activity are specifically required for the AMPK alpha 1 SUMOylation and the inhibition of AMPK alpha 1 activity towards mTORC1 signalling. The activity of a SUMOylation-deficient AMPK alpha 1a mutant is higher than the wild type towards mTORC1 signalling when reconstituted in AMPKa-deficient cells. PIAS4 depletion reduced growth of breast cancer cells, specifically when combined with direct AMPK activator A769662, suggesting that inhibiting AMPK alpha 1 SUMOylation can be explored to modulate AMPK activation and thereby suppress cancer cell growth.
  • Boussios, Stergios; Mikropoulos, Christos; Samartzis, Eleftherios; Karihtala, Peeter; Moschetta, Michele; Sheriff, Matin; Karathanasi, Afroditi; Sadauskaite, Agne; Rassy, Elie; Pavlidis, Nicholas (2020)
    Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer mortality among women. Two-thirds of patients present at advanced stage at diagnosis, and the estimated 5 year survival rate is 20-40%. This heterogeneous group of malignancies has distinguishable etiology and molecular biology. Initially, single-gene sequencing was performed to identify germline DNA variations associated with EOC. However, hereditary EOC syndrome can be explained by germline pathogenic variants (gPVs) in several genes. In this regard, next-generation sequencing (NGS) changed clinical diagnostic testing, allowing assessment of multiple genes simultaneously in a faster and cheaper manner than sequential single gene analysis. As we move into the era of personalized medicine, there is evidence that poly (ADP-ribose) polymerase (PARP) inhibitors exploit homologous recombination (HR) deficiency, especially in breast cancer gene 1 and 2 (BRCA1/2) mutation carriers. Furthermore, extensive preclinical data supported the development of aurora kinase (AURK) inhibitors in specific tumor types, including EOC. Their efficacy may be optimized in combination with chemotherapeutic or other molecular agents. The efficacy of metformin in ovarian cancer prevention is under investigation. Certain mutations, such as ARID1A mutations, and alterations in the phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR pathway, which are specific in ovarian clear cell carcinoma (OCCC) and endometrioid ovarian carcinoma (EnOC), may offer additional therapeutic targets in these clinical entities. Malignant ovarian germ cell tumors (MOGCTs) are rare and randomized trials are extremely challenging for the improvement of the existing management and development of novel strategies. This review attempts to offer an overview of the main aspects of ovarian cancer, catapulted from the molecular mechanisms to therapeutic considerations.
  • Khatun, Masuma; Arffman, Riikka K.; Lavogina, Darja; Kangasniemi, Marika; Laru, Johanna; Ahtikoski, Anne; Lehtonen, Siri; Paulson, Mariana; Hirschberg, Angelica Linden; Salumets, Andres; Andersson, Leif C.; Piltonen, Terhi T. (2020)
    Stanniocalcin-1 (STC-1) is a pro-survival factor that protects tissues against stressors, such as hypoxia and inflammation. STC-1 is co-expressed with the endometrial receptivity markers, and recently endometrial STC-1 was reported to be dysregulated in endometriosis, a condition linked with endometrial progesterone resistance and inflammation. These features are also common in the endometrium in women with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women. Given that women with PCOS present with subfertility, pregnancy complications, and increased risk for endometrial cancer, we investigated endometrial STC-1 expression in affected women. Endometrial biopsy samples were obtained from women with PCOS and controls, including samples from overweight/obese women with PCOS before and after a 3-month lifestyle intervention. A total of 98 PCOS and 85 control samples were used in immunohistochemistry, reverse-transcription polymerase chain reaction, or in vitro cell culture. STC-1 expression was analyzed at different cycle phases and in endometrial stromal cells (eSCs) after steroid hormone exposure. The eSCs were also challenged with 8-bromo-cAMP and hypoxia for STC-1 expression. The findings indicate that STC-1 expression is not steroid hormone mediated although secretory-phase STC-1 expression was blunted in PCOS. Lower expression seems to be related to attenuated STC-1 response to stressors in PCOS eSCs, shown as downregulation of protein kinase A activity. The 3-month lifestyle intervention did not restore STC-1 expression in PCOS endometrium. More studies are warranted to further elucidate the mechanisms behind the altered endometrial STC-1 expression and rescue mechanism in the PCOS endometrium. Summary sentence Endometrial expression of STC-1 in the secretory phase is blunted in women with PCOS, suggesting impaired protection against stress.