Betydelsen av könshormoner på metabola syndromet och akut hjärtinfarkt: En prospektiv studie i Skaraborg (ISHMI-studien).
Project number : 158711
Created by: Bledar Daka, 2014-11-06
Last revised by: Carin Sjöström-Greenwood, 2019-08-09
Project created in: FoU i Västra Götalandsregionen

PublishedPublished

1. Översiktlig projektbeskrivning

Engelsk titel

The Impact of Sex Hormones on metabolic syndrome and acute Myocardial Infarction: A prospective study in Skaraborg.(ISHMI-study)

Populärvetenskaplig sammanfattning av projektet

Bakgrund. Hos äldre män låg testosteron och hög östradiol är förknippad med högre risk för hjärtkärl-relaterade mortalitet. Hos kvinnor, sambandet mellan halter av könshormoner och risken för hjärt- och kärlsjukdomar är fortfarande osäkert. Även om det finns bevis som kopplar hjärtkärlsjukdomar med könshormon koncentrationer, bakomliggande mekanismer är fortfarande okänd.

Syftet med studien är att undersöka sambandet mellan förändringar i koncentration av könshormoner och kardiovaskulär risk och samvariationen mellan koncentrationer i könshormoner och riskfaktorer för kardiovaskulär sjukdomar hos män och kvinnor.

Metod Prospektiv observationell studie i en representativ kohort som följs upp med registerdata från sjukhus inläggningar och dödsorsaksregister. Återundersökningar med för att samla information om risk faktorer genomförs också löpande. Detta inkluderar och observationer i förändringar i blodtryck samt kärlelasticitetsförändringar.

Förväntat resultat Studien förväntas ge bättre förståelse i hur könshormoner påverkar risken att utveckla kardiovaskulär sjukdom men också sambandet med riskfaktorer för kardiovaskulär sjukdom. Kunskapet är viktigt för att identifiera individer i hög risk för utveckling av kardiovaskulär sjukdom och för att utveckla strategier att minska den här risken.

Vetenskaplig sammanfattning av projektet

In older men low testosterone and high estradiol levels are associated with higher risk of CVD-related death. In women the role of testosterone and estradiol regarding CVD risk are still uncertain. Although there is evidence that links CVD with sex hormone concentrations, the underlying mechanisms are still unknown. The main aim of the study is to evaluate the association between changes in concentration of sex hormones and the cardiovascular risk.

Baseline information of VARA-SKÖVDE COHORT have been described elsewhere. 10 years follow-up includes:
1.Standard questionnaires for previous hospitalizations, medications, smoking and alcohol habits, leisure time physical activity (LTPA), psychological and social status, menopause and symptoms related to testosterone deficiency.
2.Measurements of metabolic status with F-p-glucose, OGTT in subjects without known diabetes, HbA1C, total cholesterol, LDL, HDL
3.The standard physical examination included measurements of height, weight, waist circumference, and waist hip ratio, blood pressure after 5 minutes at rest ECG and pulse wave measurements. Participants were stratified by gender in 5-year age groups.
4.All participants were followed from the baseline examination until a first cardiovascular event or death, or otherwise until June 30, 2012. All events were retrieved by data linkage with the Swedish Cause of Death and Hospital Discharge Registers, which is a reliable validated alternative to revised hospital discharge and death certificates.
Expected Findings: The investigation of the effects of changes in testosterone and estradiol concentration would bring important information on whether an intervention altering these levels could have beneficial effects on CVD. We hope to find tools to better identify and treat subjects at higher risk earlier than we can today, and to indicate potential sites for the development of new pharmaceuticals.

Baseline information of VARA-SKÖVDE COHORT have been described elsewhere. 10 years follow-up includes:
1.Standard questionnaires for previous hospitalizations, medications, smoking and alcohol habits, leisure time physical activity (LTPA), psychological and social status, menopause and symptoms related to testosterone deficiency.
2.Measurements of metabolic status with F-p-glucose, OGTT in subjects without known diabetes, HbA1C, total cholesterol, LDL, HDL
3.The standard physical examination included measurements of height, weight, waist circumference, and waist hip ratio, blood pressure after 5 minutes at rest ECG and pulse wave measurements. Participants were stratified by gender in 5-year age groups.
4.All participants were followed from the baseline examination until a first cardiovascular event or death, or otherwise until June 30, 2012. All events were retrieved by data linkage with the Swedish Cause of Death and Hospital Discharge Registers, which is a reliable validated alternative to revised hospital discharge and death certificates.
Expected Findings: The investigation of the effects of changes in testosterone and estradiol concentration would bring important information on whether an intervention altering these levels could have beneficial effects on CVD. We hope to find tools to better identify and treat subjects at higher risk earlier than we can today, and to indicate potential sites for the development of new pharmaceuticals.

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva typ av studier

checked Longitudinella studier (Longitudinal Studies)
checked Prospektiva studier (Prospective Studies)


(Only selected options are displayed. Click here to display all options)

MeSH-termer för att beskriva ämnesområdet

information Added MeSH terms
Testosterone
A potent androgenic steroid and major product secreted by the LEYDIG CELLS of the TESTIS. Its production is stimulated by LUTEINIZING HORMONE from the PITUITARY GLAND. In turn, testosterone exerts feedback control of the pituitary LH and FSH secretion. Depending on the tissues, testosterone can be further converted to DIHYDROTESTOSTERONE or ESTRADIOL.
Myocardial Infarction
NECROSIS of the MYOCARDIUM caused by an obstruction of the blood supply to the heart (CORONARY CIRCULATION).
Estradiol
Generally refers to the 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids. In humans, it is produced primarily by the cyclic ovaries and the PLACENTA. It is also produced by the adipose tissue of men and postmenopausal women. The 17-alpha-isomer of estradiol binds weakly to estrogen receptors (RECEPTORS, ESTROGEN) and exhibits little estrogenic activity in estrogen-responsive tissues. Various isomers can be synthesized.
Sex Hormone-Binding Globulin
A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as ANDROGEN-BINDING PROTEIN. They differ by their sites of synthesis and post-translational oligosaccharide modifications.

Projektets delaktighet i utbildning

checked Avhandling


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2. Projektorganisation och finansiering

Arbetsplatser involverade i projektet

information Added workplaces
Annan
Kvartersklinken/Primärvården Göteborg/ Västra Götaland Region
Regioner - Västra Götalandsregionen - Närhälsan - Rehabilitering - Område R9 - Närhälsan Skövde rehabmottagning - Ekedalsgatan - Övrigt
Regioner - Västra Götalandsregionen - Specialiserad vård - Sahlgrenska Universitetssjukhuset - Område 6 - Medicin, Sahlgrenska workplace verified by Västra Götalandsregionen on 2018-02-27
Regioner - Västra Götalandsregionen - Närhälsan - Vårdcentraler - Område V5 - Närhälsan Ekmanska vårdcentral (Göteborg) workplace verified by Västra Götalandsregionen on 2018-02-27

Coworker

Ulf Lindblad
Professor emeritus/ distriktsläkare, Närhälsan Hentorp vårdcentral (Skövde), Närhälsan FoU-centrum Göteborg och Södra Bohuslän, Enheten för Allmänmedicin
Thord Rosén
Docent, överläkare, Endokrinsektionen, Medicinkliniken, Sahlgrenska
Per-Anders Jansson
Professor, överläkare, Göteborg, Avdelningen för molekylär och klinisk medicin
Maria Eriksson
leg. psykolog och doktorand i allmänmedicin, Capio Vårdcentral Hovås, Närhälsan FoU-centrum Göteborg och Södra Bohuslän, Avdelningen för samhällsmedicin och folkhälsa
Margareta Hellgren
distriktsläkare, Närhälsan Södra Ryd vårdcentral (Skövde)
Kristin Ottarsdottir
Specialistläkare allmänmedicin, Närhälsan FoU-centrum Göteborg och Södra Bohuslän, Närhälsan Lerum vårdcentral, Avdelningen för samhällsmedicin och folkhälsa

Finansiering

Grants

Regionala FoU-medel Västra Götalandsregionen (571681) the grant is verified by a Researchweb® grant provider
306 000 SEK
Bledar Daka, Ulf Lindblad, Margareta Hellgren, Kristin Ottarsdottir, Maria Eriksson

2015, The Impact of Sex Hormones on metabolic syndrome and acute Myocardial Infarction: A prospective study in Skaraborg

Regionala FoU-medel Västra Götalandsregionen (483741) the grant is verified by a Researchweb® grant provider
285 000 SEK
Bledar Daka, Thord Rosén, Per-Anders Jansson, Margareta Hellgren, Maria Eriksson

2014, The Impact of Sex Hormones on metabolic syndrome and acute Myocardial Infarction: A prospective study in Skaraborg.(ISHMI-study)

Regionala FoU-medel Västra Götalandsregionen (389221) the grant is verified by a Researchweb® grant provider
279 000 SEK
Bledar Daka, Margareta Hellgren, Maria Eriksson, Ulf Lindblad, Thord Rosén

2013, The Impact of Sex Hormones on metabolic syndrome and acute Myocardial Infarction: A prospective study in Skaraborg.(ISHMI-study)

3. Processen och projektets redovisning

Publikationer från detta projekt

Detaljerad projektbeskrivning

Bakgrundsbeskrivning

Serum concentrations of testosterone in men decrease with age[1]. Although the decrease may partially be attenuated by increasing levels of sex hormone binding globulin (SHBG)[2], obesity has an independent major impact on the decrease of these levels[3]. On the other hand prospective studies have shown that low serum levels of testosterone can independently predict both obesity and diabetes[4]. The link between concentrations of serum testosterone and type 2 diabetes has become a topic of debate as two prospective studies have shown that SHBG independently can predict T2D[5,6].
In elderly populations low concentrations of testosterone predict both all cause and cardiovascular mortality[7-9]. There is an on-going debate whether concentrations of serum testosterone are a marker of aging in men, or if they influences the aging process and atherosclerosis[10]. Studies conducted in men following an acute myocardial infarction have demonstrated that testosterone induces vasodilatation, thus increasing coronary artery perfusion[11]. Accelerated atherosclerosis is observed in elderly castrated men[12]. A recent trial investigating the effects of testosterone replacement therapy (TRT) in patients with type 2 diabetes has shown beneficial effects on insulin resistance (HOMA-ir) and on LDL-cholesterol[13].
Besides the general question of associations in people with diabetes, knowledge is limited with regard to the association between testosterone and cardiovascular risk in women, and previous results are inconsistent[14-16].
Against this background we investigated the associations between endogenous testosterone concentrations and the incidence of acute myocardial infarction in men and women with type 2 diabetes, and found that low testosterone levels in men with type 2 diabetes are associated with higher rate of AMI.
Although the association of testosterone with CVD dead and CVD morbidity have now replicated in several cohorts the mechanisms lying behind are still unclear.

Syfte

Variations in the concentration of sex hormones have been associated to CVD. The mechanisms behind these associations are still to a large extent unknown. Using a longitudinal design, the main aim of the project will be to investigate to what degree changes in sex hormone concentrations contribute to the risk of MI.
Ultimately we aim to improve strategies for prevention and risk factor control in clinical practice.
Specific aims

1. Do changes in concentration of sex hormones predict the development of acute myocardial infarction? If so, are there discrepancies between men and women?
2. What factors influence change in the concentration of sex hormones? Are there discrepancies between men and women?
3. Do genes coding for sex hormones, and in particular SHBG, contribute with any further explanation on the risk of myocardial infarction when the effects of sex hormones are accounted for in multivariate analyses? If so, are there discrepancies between men and women?
4. Are sex hormones and changes in their concentration related to changes in endothelial function? May such an effect contribute to the risk of myocardial infarction? If so, are there discrepancies between men and women?
5. How does impaired glucose metabolism modify the relations found in aim 1 – 4?

Frågeställning / Hypoteser

The central question to answer in our project is if changes in concentrations of sex hormones are associated with cardiovascular risk. Although the association between the CVD risk and concentration of sex hormones is observed in several studies, the mechanisms of this association are unknown. Our hypothesis is that the decrease on the sex hormone concentrations is associated with poor metabolic control and increase on arterial stifness independent of age.

Teoretisk referensram

1.Vermeulen A, Rubens R, Verdonck L: Testosterone secretion and metabolism in male senescence. J Clin Endocrinol Metab 1972, 34(4):730-735.
2.Harman SM, Metter EJ, Tobin JD, Pearson J, Blackman MR: Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 2001, 86(2):724-731.
3.Zumoff B, Strain GW, Miller LK, Rosner W, Senie R, Seres DS, Rosenfeld RS: Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity. J Clin Endocrinol Metab 1990, 71(4):929-931.
4.Oh JY, Barrett-Connor E, Wedick NM, Wingard DL: Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care 2002, 25(1):55-60.
5.Ding EL, Song Y, Manson JE, Hunter DJ, Lee CC, Rifai N, Buring JE, Gaziano JM, Liu S: Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med 2009, 361(12):1152-1163.
6.Lakshman KM, Bhasin S, Araujo AB: Sex hormone-binding globulin as an independent predictor of incident type 2 diabetes mellitus in men. J Gerontol A Biol Sci Med Sci 2010, 65(5):503-509.
7.Laughlin GA, Barrett-Connor E, Bergstrom J: Low serum testosterone and mortality in older men. J Clin Endocrinol Metab 2008, 93(1):68-75.
8.Tivesten A, Hulthe J, Wallenfeldt K, Wikstrand J, Ohlsson C, Fagerberg B: Circulating estradiol is an independent predictor of progression of carotid artery intima-media thickness in middle-aged men. J Clin Endocrinol Metab 2006, 91(11):4433-4437.
9.Tivesten A, Vandenput L, Labrie F, Karlsson MK, Ljunggren O, Mellstrom D, Ohlsson C: Low serum testosterone and estradiol predict mortality in elderly men. J Clin Endocrinol Metab 2009, 94(7):2482-2488.
10.Miner MM, Seftel AD: Testosterone and ageing: what have we learned since the Institute of Medicine report and what lies ahead? International journal of clinical practice 2007, 61(4):622-632.
11.Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P: Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999, 100(16):1690-1696.
12.Muller M, van den Beld AW, Bots ML, Grobbee DE, Lamberts SW, van der Schouw YT: Endogenous sex hormones and progression of carotid atherosclerosis in elderly men. Circulation 2004, 109(17):2074-2079.
13.Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, Morales AM, Volterrani M, Yellowlees A, Howell JD et al: Testosterone replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome (the TIMES2 study). Diabetes Care 2011, 34(4):828-837.
14.Barrett-Connor E, Goodman-Gruen D: Prospective study of endogenous sex hormones and fatal cardiovascular disease in postmenopausal women. Bmj 1995, 311(7014):1193-1196.
15.Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, Kelsey SF, Kip KE, Cooper-Dehoff RM, Johnson BD et al: Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation. J Clin Endocrinol Metab 2008, 93(4):1276-1284.
16.Sievers C, Klotsche J, Pieper L, Schneider HJ, Marz W, Wittchen HU, Stalla GK, Mantzoros C: Low testosterone levels predict all-cause mortality and cardiovascular events in women: a prospective cohort study in German primary care patients. Eur J Endocrinol 2010, 163(4):699-708.
17.Wehr E, Pilz S, Boehm BO, Grammer TB, Marz W, Obermayer-Pietsch B: Low free testosterone levels are associated with all-cause and cardiovascular mortality in postmenopausal diabetic women. Diabetes Care 2011, 34(8):1771-1777.
2007, 92(2):405-413.

Metod: Urval

A cross-sectional population survey from Vara and Skövde (VSC) 2001-2005 (n=2816, aged 30-74 years). In Vara 1811 participants were enrolled (81% participation rate), and in Skövde the survey included 1005 subjects (70%). A 10-year follow-up has started and almost 50% of the cohort have already been followed with teh same procedure as at baseline.

Metod: Datainsamling

Standard questionnaires are used to gain information on previous hospitalizations, on smoking and alcohol habits as well as on leisure time physical activity. Data on demographic and socio-economic factors of importance for the development of heart disease are gathered using questionnaires developed in our department. Standard instruments are also used for the collection of data on social networks and social stress, and symptoms of anxiety and depression. The nurses collect the questionnaires and help to complete missing data.
The nurses measure standard resting blood pressure two times 1 minute apart after five minutes rest with the subjects in a supine position, and after 1 minute in a standing position. (Right brachial artery, arm in heart level, cuff size adjusted for arm circumference, and reading the pressure at the closest 2 mmHg). A 12-lead computerized resting ECG is recorded to characterize the left ventricular hypertrophy (LVH), ischemia, arrhythmia, QTc and heart rate variability. We defined left ventricular hypertrophy from the Minnesota-coded electrocardiograms. Body mass index (BMI) and waist hip circumferences are measured.
Samples including plasma and serum are drawn after an over night fasting immediately frozen at –82 degrees C. An oral glucose tolerance test (OGTT), administering a standard 75 g glucose load is performed and samples drawn at 0 and 2h. In participants 50 years an additional sample is drawn at 30 minutes. The OGTT is used to characterize the participants with respect to impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and diabetes mellitus (DM). Insulin secretion and insulin sensitivity is estimated using the HOMA indexes, and for insulin secretion also the increment during the first 30 minutes of the OGTT. Glycosylated haemoglobin (HbA1c) level is analyzed using standard procedures. Serum cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, free fatty acids (FFA), apolipoprotein B and A will be analyzed. Further phenotypic characterization includes s-testosteron, oestradiol, and SHBG measured with one-step competitive immunoassay with ALP and magnetic separation. Night urine is used to determine the excretion rate of microalbuminuria
End-points of the study include all fatal events of AMI. Information on these end-points from baseline will be ascertained by record linkage with the Swedish national mortality and the inpatient register. All variables studied in relation to mortality refer to the risk factor evaluation at the baseline examination. The time available for follow-up is now 17 years.
Secondary endpoints will be changes in metabolic control (differences in Homa-ir) and in bloodpressure and artery stiffness.

Metod: Databearbetning

SPSS 20 will be used for statistical analysis and standard methods will be used for descriptive purposes. General linear models and logistic regression will be used for continuous and categorical variables, respectively. Kaplan Mayer curves and Cox regressions will be used for survival analyses. All tests are two-sided and statistical significance are assumed when p0.05.


Betydelsen av könshormoner på metabola syndromet och akut hjärtinfarkt: En prospektiv studie i Skaraborg (ISHMI-studien)., from FoU i Västra Götalandsregionen
http://www.researchweb.org/is/html/vgr/project/158711