Menopause, Metabolic Syndrome and Obesity Prof Mary Ann Lumsden Prof of Gynaecology and Medical Education February 2013

Mortality Rates in Women National Center for Health Statistics. 1999: Coronary Artery Disease Stroke Lung Cancer Breast Cancer Colon Cancer Endometrial Cancer Age (years) Mortality Rate per 100,

England & Wales Bangladesh India Pakistan West Africa West Indies China & Hong Kong Standardised Mortality Ratio (SMR) Women Men IHD mortality (ICD ) by country of birth S Wild, unpublished data

Medical Complications of Obesity Phlebitis venous stasis Venous thrombosis Coronary heart disease Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome Gall bladder disease Gout Diabetes Osteoarthritis Nonalcoholic fatty liver disease Steatosis/ steatohepatitis cirrhosis Hypertension Dyslipidemia Cataracts Oedema Pancreatitis Idiopathic intracranial hypertension + Loss of vision CANCER breast, uterus, cervix, prostate, kidney colon, esophagus, pancreas, liver Gynecologic abnormalities abnormal menses / infertility polycystic ovarian syndrome gestational diabetes pre-eclampsia Stroke Tiredness Back pain

High risk groups Diabetes Metabolic syndrome Obesity Polycystic ovary syndrome Hypertension Premature menopause History of pre-eclampsia

Obesity among kuwaitis over 50

Body Mass Index Badr et al 2012

Fat Distribution

Perimenopausal Weight Gain Lovejoy et al 2008

Body Fat Changes in the Menopause

Body composition menopause *** ***p<0.001 Ley et al. Am J Clin Nutr 1992; 55: Android fatGynoid fat

Menopause and the Metabolic Syndrome SWAN Study 949 women 9 yr. f-u from pre- to post- menopause Janssen I, et al. Arch Intern Med 2008;168:1568 waist circ. FMP

Waist/hip ratio BMI (kg/m2) SA n=1420 European n= 1515 Fat is in the wrong place! (Adapted from McKeigue et al, with permission from authors) Other evidence for increase visceral fat mass Other evidence for increase visceral fat mass

30.0Body mass index (kg/m 2 ) Waist to hip ratio1.20 Female A Pear-shaped body Premenopause Female B Apple-shaped body Postmenopause

HRT Some studies suggest that it maintains the ‘gynoid’ fat distribution but this has not been shown conclusively

South AsiansWhite Europeansp N4640 Age (y)54.7± ± BMI25.8± ± HbA1c (mmol/mol)37.6± ±3.5<0.001 Fasting Glucose (mmol/l) 5.01±0.64.9± LDL (mmol/l)3.86± ± HDL (mmol/l)1.38±0.31.7± SBP (mmHg)125.9± ± Waist to Hip Ratio0.84± ± Metabolic features of a group of healthy European and South Asian women who reside in the UK

Fat distribution and ethnicity SAs (ethnicity=1) are more centrally obese for the same BMI than Europeans, but fat distribution in the upper or lower body do not differ P<0.001 mm

NEFA, leptin, IL- 6, TNF , resistin release NEFA, leptin, IL- 6, TNF , resistin release Adiponectin release Adiponectin release SKELETALMUSCLE Oxidative capacity Capacity for fatty acid utilisation Evidenced by: - Decreased activities of enzymes regulating oxidative/fatty acid metabolism and increased activities of glycolytic enzymes.  Increased muscle LCACoA concentrations  Reduced fat oxidation at rest and during exercise  Reduced exercise capacity ADIPOSE TISSUE TISSUE INSULINRESISTANCE Effect on muscle metabolism? Innate defect within muscle? Do South Asians metabolize fat less efficiently

Why do women put on Weight? Eat more? Less Exercise? Altered metabolism? Combination of the above?

Food plentiful –hard to resist

Healthy Food and Exercise – or not!

Metabolic Syndrome

Metabolic Syndrome and BMI

MS Components by gender Al Zenki et al 2012

NCEP-ATPIIIWHO Metabolic syndrome definitions Age standardised prevalence (%) European South Asian Overall prevalence of metabolic syndrome in South Asians

 IL-6  CRP  ALT  TG,  HDL IRSkeletalmuscle Genes  FA  PAI-1 +ve  leptin  adiponectin EnvironmentAging Centralobesity Steroids, Ang II Hypertension Fat cells release many things

Hot Flushing and Cardiovascular Disease

Flushing and cardiovascular disease In WHI, incident CHD concentrated among older women reporting VSM. Oestrogen withdrawal has significant impact on blood vessel structure and function. Oestrogen improves endothelial function. Oestrogen use is associated with fewer calcified plaques in the coronary arteries. Calcitonin gene-related peptide is released during flushing but not during exercise or sweating. Obesity and smoking are risk factors for heart disease and flushing

Vasomotor Symptoms and CVD Rancho Brando Study (Svartberg et al 2009) HR 0.72( ) in favour of flushing. Gast et al over 10,000 Dutch Women (HR 1.33 ( ). Largely explained by cholesterol levels Hot Flushing and Cardiovascular Disease

SWAN Study Study of Women’s Health Across the Nation (SWAN) Study 3302 participants across 7 sites (42-52 years of age). 588 women in ‘Heart’ Study. 491 gave information on flushing (assessed according to number of days on which flushes occurred in previous 14 days) 374 had USS to assess flow-mediated dilatation (FMD) or assessment of coronary artery calcification Heart participants were Caucasian or African-American

NON-FLUSHERSFLUSHERS Number Age50.0 (2.8)50.7 (2.9) Postmenopausal18.6%39.7% BMI kg/m228.6 (6.1)29.8 (6.2) HDL mg/dl56.4 ((14.4)58.1 (13.9) LDL mg/dl116.1 (32.0)122.3 (32.3) Aortic Calcification Score ** 086 (35%)52 (23.7) >0 - <1061 (24.7)60 (27.3) >10%41 (16.6)58 (26.4) FSH mIU/ml39.8 (35.6)48.3 (69.5) SWAN Study, Cardiovascular Risk and Flushing

NON-FLUSHERSFLUSHERS Number Age50.0 (2.8)50.7 (2.9) Postmenopausal18.6%39.7% BMI kg/m228.6 (6.1)29.8 (6.2) HDL mg/dl56.4 ((14.4)58.1 (13.9) LDL mg/dl116.1 (32.0)122.3 (32.3) Aortic Calcification Score ** 086 (35%)52 (23.7) >0 - <1061 (24.7)60 (27.3) >10%41 (16.6)58 (26.4) FSH mIU/ml39.8 (35.6)48.3 (69.5) SWAN Study, Cardiovascular Risk and Flushing

Cardiovascular Risk Factors in women who flush : Lipids p= 0.91 Adjusted p= 0.97 p<0.001 Adjusted p<0.001 p= 0.01 Adjusted p= 0.01 p= 0.29 Adjusted p= 0.29 p= 0.83 Adjusted p= 0.97 p= 0.23 Adjusted p= 0.29

Cardiovascular Risk Factors in women who flush: Inflammatory markers p= 0.59 Adjusted p= 0.67 p= 0.07 Adjusted p= 0.18 p= 0.38 Adjusted p= 0.48 p= 0.68 Adjusted p= 0.69 p= 0.02 Adjusted p= 0.05

Obesity, Cardiovascular Disease and the Menopause A problem for all and particularly middle aged women.