International Textbook of Obesity - part 6 pdf

256 INTERNATIONAL TEXTBOOK OF OBESITY fects multiple tissues, and the following evidence has been obtained that it results in attenuated glucocorticoid action in liver, brain and possibly peripheral fat In the liver, PEPCK, the rate-limiting enzyme in gluconeogenesis which is downregulated by insulin and upregulated by glucocorticoids, shows an impaired induction in response to fasting in 11 -HSD / animals (Figure 18.6c) This is consistent with the interpretation of pharmacological experiments (see above) that 11 -HSD1 maintains intrahepatic glucocorticoid receptor activation When 11 -HSD1 / animals are fed a highfat cafeteria diet, they gain less weight and have lower plasma glucose levels than wild-type controls The latter is consistent with effects on the hepatic gluconeogenic response to insulin, but the former may be explained by additional central effects of 11 -HSD1 on regulation of energy expenditure and/or an influence of 11 -HSD1 on adipocyte metabolism Appetite and energy expenditure have yet to be examined Interestingly, however, body fat distribution in animals on normal chow is not obviously different from wild type 11 -HSD1 / mice are also hyper-corticosteronaemic, consistent with a defect in negative feedback regulation of the hypothalamic-pituitaryadrenal axis -Reductase Knockout Mice Mice with transgenic deletion of both isozymes of -reductase have been reported (86,153) The reductase type knockout, surprisingly, has no abnormality of prostate or genital development but in rodents -reductase type is co-expressed and could compensate The -reductase type knockout also has no major phenotypic abnormality, except an increased risk of in utero death attributed to diversion of androgens to oestrogens instead of -dihydrotestosterone (86) However, glucocorticoid metabolism and action has not been reported in these animals Pharmacological Manipulation Liquorice and its Derivatives Extracts from the liquorice root have been used as confectionery and in therapy for dyspepsia for dec- ades (154) Some people habitually consume excessive quantities of liquorice, although whether there is a liquorice withdrawal syndrome—suggesting that the material is truly ‘addictive’—has not been established The active constituents of liquorice include glycyrrhizic acid and its metabolite glycyrrhetinic acid (Figure 18.9) A related hemisuccinate, carbenoxolone, remains a licensed medication for dyspepsia in UK A long-recognized side effect of liquorice ingestion is sodium retention, leading to hypertension and even heart failure This is accompanied by hypokalaemia and suppression of plasma renin activity and aldosterone and was at one time attributed to direct activation of mineralocorticoid receptors by liquorice However, these side effects are dependent upon the presence of cortisol Stewart and Edwards showed that liquorice derivatives, particularly glycyrrhetinic acid, inhibit 11 -HSDs and enhance binding of glucocorticoids to mineralocorticoid receptors (24,61,63,155) Liquorice administration therefore reproduces the syndrome of apparent mineralocorticoid excess, including elevated ratios of cortisol/cortisone and of their metabolites in urine and prolonged half-life of 11 H-cortisol (Table 18.6) Further studies showed that carbenoxolone also induces cortisol-dependent mineralocorticoid excess and inhibits 11 -HSD in vitro (64) However, there were several differences between the effects of carbenoxolone and liquorice/glycyrrhetinic acid in humans (Table 18.6) While carbenoxolone increases urinary free cortisol/cortisone and prolongs the half-life of 11 H-cortisol, it does not alter ratios of A-ring reduced urinary metabolites of cortisol versus cortisone (Figure 18.8) This paradox is explained by the observation that carbenoxolone, but not liquorice, inhibits the conversion of cortisone to cortisol by 11 -HSD1 in liver (64,156) Thus, inhibition of 11 -HSD2 in kidney is balanced by inhibition of 11 -HSD1 in liver and there is no change in overall equilibrium between cortisol and cortisone despite marked changes in intrarenal and intrahepatic cortisol concentrations (125) This is an important observation to bear in mind when interpreting urinary cortisol metabolite results in other clinical syndromes (see above) As a result, carbenoxolone produces additional clinical effects, including enhancing insulin sensitivity (Figure 18.4) (67) The reasons for this discrepancy are not clear, since carbenoxolone and glycyrrhetinic acid have CORTISOL METABOLISM 257 Figure 18.9 11 -HSD inhibitors Glycyrrhetinic acid is the principal active constituent of liquorice Carbenoxolone is a synthetic hemisuccinate derivative -reductase type This is used in the treatment of benign prostatic hyperplasia and in prostatic carcinoma It has a weak effect to reduce androgen receptor activation in skin and may be useful in the treatment of hirsutism and male-pattern baldness Finasteride is relatively, but not completely, specific for the human type -reductase isozyme It has also been shown to alter cortisol metabolism in one small study (158), although the impact on glucocorticoid receptor activation was not assessed Selective -reductase type inhibitors exist (159), but have not been employed therapeutically Figure 18.10 A-ring reductase activity in human obesity The ratio -/5 -tetrahydrocortisol reflects relative activities of and -reductases This study of 68 healthy men (filled symbols) and postmenopausal women (open symbols; triangles indicate those receiving oestrogen replacement therapy) aged 47—53 years from a cross-sectional cohort study revealed higher excretion of -tetrahydrocortisol in subjects with central obesity Adapted from Andrew et al (163) similar affinities for both 11 -HSD isozymes in vitro It probably relates to pharmacokinetic factors, perhaps because carbenoxolone is water soluble whereas glycyrrhetinic acid is lipid soluble and hydrophobic The effects of liquorice derivatives are not selective for 11 -HSD enzymes These compounds also inhibit enzymes metabolizing prostaglandins (157) In addition, they inhibit -reductase in vitro (see below) (152) -Reductase Inhibitors Arguably the most successful example of therapeutic manipulation of pre-receptor ligand metabolism to date is the use of finasteride to inhibit ALTERED CORTISOL METABOLISM IN OBESITY Cortisol Metabolism in Primary Obesity Relatively small case-control studies, almost exclusively in women, showed that obesity, particularly of predominantly abdominal distribution, is associated with increased urinary free cortisol excretion (160—162) However, as detailed above, urinary free cortisol forms a very small fraction of total cortisol metabolite excretion More convicingly, recent large studies confirm that total cortisol production rate is somewhat enhanced in obesity in men as well as women (131,163,164) This is further supported by evidence of enhanced responsiveness of the hypothalamic-pituitary-adrenal axis to ACTH and CRH (161,165) However, in obesity plasma cortisol levels are not consistently elevated Indeed, peak plasma cortisol levels in the morning are low (166—169) The combination of increased secretion with low morning plasma levels suggests either that diurnal variation of cortisol secretion is disrupted, 258 INTERNATIONAL TEXTBOOK OF OBESITY or that peripheral metabolism of cortisol is enhanced Previous studies using radioisotope tracers showed that metabolic clearance rate for cortisol is indeed enhanced in obesity (170) Very recent studies have identified which specific pathways of cortisol metabolism are involved In a study of 68 men and women, we reported elevated ratios of cortisol/ cortisone metabolites in obese men and elevated excretion of -reduced metabolites in obese men and women (Figure 18.10) (163) Our finding of enhanced -reduced metabolites in obesity has been confirmed in a further independent study of nearly 500 men and women (164) and in our own unpublished observations in an additional 300 subjects It is likely that the same change explains the observation of increased -reduced cortisol metabolites in polycystic ovary syndrome (171) We have also observed increased hepatic -reductase type activity in liver of leptin-resistant, obese Zucker rats (72) However, cortisol/cortisone metabolite ratios have proved less consistent in further studies Stewart and colleagues (131) studied 36 men and women and reported that the obese group (n : 12) had impaired conversion of oral cortisone to cortisol in peripheral plasma—suggesting impaired hepatic 11 -reductase activity (Figure 18.4) This was associated with lower ratios of cortisol/cortisone metabolites, and relatively impaired inactivation of cortisol by -reductase (Figure 18.2) By contrast, Katz et al examined arteriovenous differences in cortisol/cortisone ratio across subcutaneous abdominal fat and found a trend towards increased 11 -HSD1 activity in obesity (57) A likely explanation for these discrepancies is that there are tissue-specific differences in the activity of 11 HSD type in obesity (72), with impaired conversion of cortisone to cortisol in liver but normal or enhanced conversion in adipose tissue and perhaps other sites The sum may frequently be no overall change in urinary metabolites Indeed, we have evidence in favour of such tissue-specific changes in 11 -HSD1 activity from leptin-resistant obese Zucker rats (72) We have therefore proposed that in obesity enhanced cortisol clearance by -reductase may lower plasma cortisol levels, thereby reducing negative feedback and providing a key stimulus to the hypothalamic-pituitary-adrenal axis Such enhanced cortisol clearance will be exacerbated by impaired regeneration of cortisol from cortisone by reduced 11 -HSD1 in liver However, this results in an elevated pool of cortisol metabolites, including cortisone, available for potential reactivation In tissues where 11 -HSD1 activity is maintained or even enhanced (e.g adipose tissue), the local cortisol levels may be elevated in the face of overall increased metabolic clearance rate (Figure 18.11) At present we can only speculate on the mechanism of altered cortisol metabolism in obesity The regulation of relevant enzymes by hormones which are disturbed in obesity is clearly relevant (Table 18.4), but none of these have yet been manipulated in obese subjects to assess reversibility of the dysregulation of cortisol metabolism Cortisol Metabolism and Growth Hormone Deficiency Adult growth hormone deficiency is associated with a syndrome which includes lethargy, dyslipidaemia and central obesity The mechanisms whereby growth hormone and insulin-like growth factor (IGF-1) influence body fat distribution are poorly characterized, and may be mediated indirectly by changes in glucocorticoid receptor activation In growth-hormone deficient rats, female pattern (continuous administration) growth hormone replacement potently downregulates hepatic 11 -HSD1 expression (172) By contrast, male pattern (pulsatile) growth hormone does not affect enzyme activity Similar effects of growth hormone and IGF-1 have been reported in human adipose stromal cells in primary culture In humans, evidence is restricted to interpretation of urinary cortisol metabolites, and studies in hypopituitary patients are confounded by the effect of oral cortisol replacement therapy However, it appears that continuous (daily subcutaneous injection) growth hormone replacement inhibits 11 -HSD1 on the basis that cortisol/ cortisone metabolite ratios are lower and urinary free cortisol/cortisone ratios either unchanged or elevated (173—175) Thus, growth hormone deficiency may well be associated with enhanced adipose 11 -HSD1 and higher intra-adipose cortisol concentrations It is an intriguing speculation that many of the benefits of growth hormone replacement in adult hypopituitary patients—reduced central adiposity, normalization of dyslipidaemia, and CORTISOL METABOLISM Figure 18.11 A model of consequences of tissue-specific changes in cortisol metabolism in obesity Figure 18.12 Interaction of increasing plasma cortisol and obesity in predicting blood pressure Data are from 226 otherwise healthy men and women from the MONICA cross-sectional cohort study in northern Sweden Obesity in this population is associated with lower 0900 h plasma cortisol concentrations, but both obesity and higher plasma cortisol are independently associated with higher blood pressure This emphasizes that the mechanisms underlying elevated cortisol concentrations in hypertension are likely to be different from those in obesity, and it is those obese subjects who fail to show a characteristic fall in plasma cortisol levels who may be subject to the greatest metabolic complications Adapted from Walker et al (167) enhanced insulin sensitivity—might perhaps be achieved at no cost by lowering the replacement dose of oral hydrocortisone! Interactions Between Cortisol, Obesity and Other Cardiovascular Risk Factors Cushing’s syndrome is characterized not only by central obesity, but also by hypertension, dyslipidaemia, insulin resistance, and glucose intolerance This cluster of clinical features bears remarkably similarity to the cluster which occurs in the 259 metabolic syndrome (Reaven’s syndrome X; the insulin resistance syndrome) It is possible that a more subtle increase in cortisol action explains the association between these features of the metabolic syndrome and obesity In case-control and cross-sectional studies, high blood pressure is associated with elevated cortisol concentrations (in blood, saliva or urine) (164,168,176—179), impaired peripheral inactivation of cortisol by 11 -HSD2 (127,151), and enhanced tissue sensitivity to glucocorticoids as measured by the intensity of dermal vasoconstriction following topical application of beclomethasone (179,180) Similarly, insulin resistance and glucose intolerance are associated with higher circulating cortisol levels (169) and increased dermal vasoconstrictor sensitivity to beclomethasone (179,180) Higher morning plasma cortisol concentrations and increased responsiveness to ACTH also occur in adults with the additional cardiovascular risk factor of low birthweight (169,181) However, all of these associations between cortisol activity and hypertension/insulin resistance are independent of obesity Obesity is associated with lower (not higher) plasma cortisol, no change in 11 -HSD2 (rather, alterations in 11 HSD1; see above), and no difference in dermal responses to glucocorticoids From these observational studies it is not possible to dissect causality but they not favour a proposed unifying hypothesis (182) which ascribes the associations between obesity and other features of the metabolic syndrome X to enhanced cortisol secretion Rather, there may be a primary increase in hypothalamic-pituitary-adrenal axis activity and tissue sensitivity to glucocorticoids in subjects with hypertension/insulin resistance which does not directly predispose to obesity However, if these individuals become obese, then perhaps acquired changes in -reductase and 11 -HSD1 activities result in higher local glucocorticoid concentrations and amplification of hypertension and insulin resistance In support of this concept of ‘amplification’ by obesity, the highest blood pressure in crosssectional studies occurs amongst relatively rare individuals who are most obese but who have the highest morning plasma cortisol (167,169) (Figure 18.12) Therapeutic Opportunities No matter whether the changes in cortisol metab- 260 INTERNATIONAL TEXTBOOK OF OBESITY olism are primary or secondary to obesity and/or its associated neurohumoral disturbances, their influence on the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor activation may be a key step in the cascade leading to adverse metabolic consequences of obesity Therefore, therapeutic intervention to reverse the tissue-specific alterations in cortisol metabolism in obesity may be extremely useful The results of experiments with 11 -HSD1 and -reductase inhibitors in obesity are awaited with interest CONCLUSIONS This chapter presents evidence that variations in cortisol metabolism play a key role in modulating cortisol secretion and action There is a clear hypothesis that these mechanisms are important in obesity, but the limitations of current methodology for assessing cortisol metabolism in vivo in humans mean that current data remain preliminary Nevertheless, the results suggest that there are tissuespecific changes in cortisol metabolism in obesity which predict enhanced glucocorticoid action in adipose tissue but not liver We suggest that these changes are secondary to the obesity but nonetheless may amplify the link between elevated cortisol activity and hypertension or insulin resistance which we have observed in other studies This area is likely to be the focus of important research in the next few years, when we will learn whether therapeutic manipulation of cortisol metabolism is to become a successful novel approach to limiting the metabolic consequences of obesity 10 11 12 13 14 ACKNOWLEDGEMENTS Our studies are supported by major grants from the British Heart Foundation and Wellcome Trust We are grateful to Dr Ruth Andrew for assistance with preparation of material for this chapter 15 16 REFERENCES Andrews RC, Walker BR Glucocorticoids and insulin resistance: old hormones, new targets Clin Sci 1999; 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65: 295—299 Berman DM, Tian H, Russell DW Expression and regulation of steroid 5alpha-reductase in the urogenital tract of the fetal rat Mol Endocrinol 1995; 9: 1561—1570 Yokoi H, Tsuruo Y, Miyamoto T, Ishimura K Steroid 5alpha-reductase type immunolocalized in the adrenal gland of normal, gonadectomized, and sex hormonesupplemented rats Histochemistry 1998; 109: 127—134 Eicheler W, Seitz J, Steinhoff M, Forssmann WG, Adermann K, Aumuller Distribution of rat hepatic steroid 5alpha-reductase as shown by immunohistochemistry Exp Clin Endocrinol Diabetes 1995; 103: 105—112 Zyirek M, Flood C, Longcope C 5alpha-Reductase activity in rat adipose tissue Proc Soc Exp Biol Med 1987; 186: 134—138 Bullock P, Gemzik B, Johnson D, Thomas P, Parkinson A Evidence from dwarf rats that growth hormone may not regulate the sexual differentiation of liver cytochrome P450 enzymes and steroid 5alpha-reductase Proc Nat Acad Sci USA 1991; 88: 5227—5231 Lephart ED, Simpson ER, Trzeciak WH Rat adrenal 5alpha-reductase mRNA content and enzyme activity are sex hormone dependent J Mol Endocrinol 1991; 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25: 626—630 Takeda Y, Miyamori I, Iki K, Inaba S, Furukawa K, Hatakeyama H, Yoneda T, Takeda R Endogenous renal 11 -hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension Hypertension 1996; 27: 197—201 Morris DJ, Lo YH, Lichtfield WR, Williams GH Impact of dietary Na; on glycyrrhetinic acid-like factors (kidney 11beta- (HSD2)-GALFs) in human essential hypertension Hypertension 1998; 31: 469—472 Lo YH, Sheff MF, Latif SA, Ribiero C, Silver H, Brem AS, Morris DJ Kidney 11 -HSD2 is inhibited by glycyrrhetinic acid-like factors in human urine Hypertension 1997; 29: 500—505 Oelkers W, Buchen S, Diederich S, Krain J, Muhme S, Schoneshofer M Impaired renal 11 -oxidation of 9alphafluorocortisol: an explanation for its mineralocorticoid potency J Clin Endocrinol Metab 1994; 78: 928—932 Conti M, Frey FJ, Escher G, Marone C, Frey BM Renal handling of prednisolone/prednisone: Effect of steroid dose and 11beta-hydroxysteroid dehydrogenase Nephrol, Dial, Transplant 1994; 9: 1622—1628 Best R, Nelson SM, Walker BR Dexamethasone and 11dehydrodexamethasone as tools to investigate the isozymes of 11 -hydroxysteroid dehydrogenase in vitro and in vivo J Endocrinol 1997; 153: 41—48 Diederich S, Hanke B, Burkhardt P, Muller M, Schoneshofer M, Bahr V, Oelkers W Metabolism of synthetic corticosteroids by 11beta-hydroxysteroid- dehydrogenases in man Steroids 1998; 63: 271—277 Li KZ, Obeyesekere VR, Krozowski ZS, Ferrari P Oxoreductase and dehydrogenase activities of the human and rat 11beta- hydroxysteroid dehydrogenase type enzyme Endocrinology 1997; 138: 2948—2952 Honour JW Steroid profiling Ann Clin Biochem 1997; 34: 32—44 Shackleton CL Mass spectrometry in the diagnosis of steroid-related disorders and in hypertension research J Steroid Biochem Mol Biol 1993; 45: 127—140 Palermo M, Shackleton CHL, Mantero F, Stewart PM Urinary free cortisone and the assessment of 11beta- hydroxysteroid dehydrogenase activity in man Clin Endocrinol 1996; 45: 605—611 Best R, Walker BR Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11 -hydroxysteroid dehydrogenase in vivo Clin Endocrinol (Oxf) 1997 47: 231—236 Ulick S, Tedde R, Wang JZ Defective ring A reduction of 125 126 127 128 129 130 131 132 133 134 135 136 137 138 cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess J Clin Endocrinol Metab 1992; 74: 593—599 Edwards CRW, Walker BR Cortisol and hypertension: what was not so apparent about ‘apparent mineralocorticoid excess’ J Lab Clin Med 1993; 122: 632—635 Walker BR How will we know if 11 -hydroxysteroid dehydrogenases are important in common diseases? Clin Endocrinol 2000; 52: 401—402 Walker BR, Stewart PM, Shackleton CHL, Padfield PL, Edwards CRW Deficient inactivation of cortisol by 11 hydroxysteroid dehydrogenase in essential hypertension Clin Endocrinol (Oxf) 1993; 39: 221—227 Mantero F, Tedde R, Opocher G, Fulgheri PD, Arnaldi G, Ulick S Apparent mineralocorticoid excess type II Steroids 1994; 59: 80—83 Linberg L, Wang JZ, Arison BH, Ulick S Synthesis of a deuterium-labeled cortisol for the study of its rate of 11 hydroxy dehydrogenation in man J Steroid Biochem Mol Biol 1991; 38: 351—357 Finken MJJ, Andrews RC, Andrew R, Walker BR Cortisol metabolism in healthy young adults: sexual dimorphism in activities of A-ring reductase but not 11-hydroxysteroid dehydrogenases J Clin Endocrinol Metab 1999; 84: 3316—3321 Stewart PM, Boulton A, Kumar S, Clark PMS, Shackleton CHL Cortisol metabolism in human obesity: impaired cortisone—cortisol conversion in subjects with central adiposity J Clin Endocrinol Metab 1999; 84: 1022—1027 Shackleton CHL, Stewart PM: The hypertension of apparent mineralocorticoid excess syndrome In: Biglieri EG, Melby JC (eds) Endocrine Hypertension New York: Raven Press, 1990: 155—173 Dave-Sharma S, Wilson RC, Harbison MD, Newfield R, Azar MR, Krozowski, ZS, Funder JW, Shackleton CL, Bradlow HL, Wei J-Q, Hertecant J, Moran A, Neiberger RE, Balfe JW, Fattah A, Daneman D, Akkurt HI, DE, Santis C, New MI Examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess J Clin Endocrinol Metab 1998; 83: 2244—2254 Oberfield SE, Levine LS, Carey RM, Greig F, Ulick S, New MI Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess J Clin Endocrinol Metab 1983; 56: 332—339 Stewart PM, Corrie JET, Shackleton CHL, Edwards CRW Syndrome of apparent mineralocorticoid excess: a defect in the cortisol-cortisone shuttle J Clin Invest 1988; 82: 340—349 Li A, Li KZ, Marui S, Krozowski ZS, Batista MC, Whorwood CB, Arnhold IP, Shackleton CL, Mendonca BB, Stewart PM Apparent mineralocorticoid excess in a Brazilian kindred: Hypertension in the heterozygote state J Hypertens 1997; 15: 1397—1402 Lovati E, Ferrari P, Dick B, Jostarndt K, Frey BM, Frey FJ, Schorr U, Sharma AM Molecular basis of human salt sensitivity: the role of the 11 -hydroxysteroid dehydrogenase type J Clin Endocrinol Metab 1999; 84: 3745—3749 Edwards CRW, Benediktsson R, Lindsay RS, Seckl JR Dysfunction of placental glucocorticoid barrier: link be- CORTISOL METABOLISM 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 tween fetal environment and adult hypertension? Lancet 1993; 341: 355—357 Kitanaka S, Tanae A, Hibi I Apparent mineralocorticoid excess due to 11beta-hydroxysteroid dehydrogenase deficiency: A possible cause of intrauterine growth retardation Clin Endocrinol 1996; 44: 353—359 Benediktsson R, Calder AA, Edwards CRW, Seckl JR Placental 11 -hydroxysteroid dehydrogenase: a key regulator of fetal glucocorticoid exposure Clin Endo-crinol 1997; 46: 161—166 Rogerson FM, Kayes KM, White PC Variation in placental type 11beta-hydroxysteroid dehydrogenase activity is not related to birth weight or placental weight Mol Cell Endocrinol 1997; 128: 103—109 Barker DJP Fetal origins of coronary heart disease Br Med J 1995; 311: 171—174 Benediktsson R, Lindsay RS, Noble J, Seckl JR, Edwards CRW Glucocorticoid exposure in utero: new model for adult hypertension Lancet 1993; 341: 339—341 Lindsay RS, Lindsay RM, Waddell BJ, Seckl JR Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 -hydroxysteroid dehydrogenase inhibitor carbenoxolone Diabetologia 1996; 39: 1299—1305 Lindsay RS, Lindsay RM, Edwards CRW, Seckl JR Inhibition of 11 -hydroxysteroid dehydrogenase in pregnant rats and the programming of blood pressure in the offspring Hypertension 1996; 27: 1200—1204 Leon DA, Koupilova I, Lithell HO, Berglund L, Mohsen R, Vagero D, Lithell UB, McKeigue PM Failure to realise growth potential in utero and adult obesity in relation to blood pressure in 50 year old Swedish men Br Med J 1996; 312: 401—406 Phillipou G, Higgins BA A new defect in the peripheral conversion of cortisone to cortisol J Steroid Biochem 1985; 22: 435—436 Taylor NF, Bartlett WA, Dawson DJ, Enoch BA Cortisone reductase deficiency: evidence for a new inborn error in metabolism of adrenal steroids J Endocrinol 1984; 102 (Suppl): 90 (Abstract) Nikkila H, Tannin GM, New MI, Taylor NF, Kalaitzoglou G, Monder C, White PC Defects in the HSD11 gene encoding 11 -hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11oxoreductase deficiency J Clin Endocrinol Metab 1993; 77: 687—691 Li A, Tedde R, Palermo M, Shackleton CL, Stewart PM Molecular basis for hypertension in the type II variant of apparent mineralocorticoid excess American Journal of Human Genetics 1998; 63: 370—379 Soro A, Ingram MC, Tonolo G, Glorioso N, Fraser R Evidence of coexisting changes in 11 -hydroxysteroid dehydrogenase and -reductase activity in patients with untreated essential hypertension Hypertension 1995; 25: 67—70 Latif SA, Conca TJ, Morris DJ The effects of the liquorice derivative, glycyrrhetinic acid, on hepatic 3alpha- and hydroxysteroid dehydrogenases and 5alpha- and -reductase pathways of metabolism of aldosterone in male rats Steroids 1990; 55: 52—58 Mala S, Mahendroo MS, Russell DW Endocrine roles of 154 155 156 157 158 159 160 161 162 163 164 165 166 167 168 169 265 steroid -reductase isozymes Proc Endocr Soc 1998; 80: OR50-1 (Abstract) Davis EA, Morris DJ Medicinal uses of licorice through the millenia: the good and plenty of it Mol Cell Endocrinol 1991; 78: 1—6 Monder C, Stewart PM, Lakshmi V, Valentino R, Burt D, Edwards CRW Licorice inhibits corticosteroid 11 -dehydrogenase of rat kidney and liver: in vivo and in vitro studies Endocrinology 1989; 125: 1046—1053 Walker BR, Edwards CRW Licorice-induced hypertension and syndromes of apparent mineralocorticoid excess Endocrinol Metab Clin N Am 1994; 23(2): 359—377 Teelucksingh S, Benediktsson R, Lindsay RS, Burt D, Seckl JR, Edwards CRW, Nan CL, Kelly R Liquorice Lancet 1991; 337: 1549 Imperato-McGinley J, Shackleton C, Orlic S, Stoner E C19 and C21 5beta/5alpha metabolite ratios in subjects treated with the 5alpha-reductase inhibitor finasteride: Comparison of male pseudohermaphrodites with inherited 5alpha-reductase deficiency J Clin Endocrinol Metab 1990; 70: 777—782 Hirsch KS, Jones CD, Audia JE, Andersson S, McQuaid L, Stamm NB, Neubauer BL, Pennington P, Toomey RE, Russell DW LY191704: A selective, nonsteroidal inhibitor of human steroid 5alpha- reductase type Proc Nat Acad Sci USA 1993; 90: 5277—5281 Strain GW, Zumoff B, Strain JJ Cortisol production in obesity Metabolism 1980; 29: 980—985 Marin P, Darin M, Amemiya T, Andersson B, Jern S, Bjorntorp P Cortisol secretion in relation to body fat distribution in obese premenopausal women Metabolism 1992; 41: 882—886 Pasquali R, Cantobelli S, Casimirri F, Capelli M, Bortoluzzi L, Flamia R, Labate AMM, Barabara L The hypothalamic-pituitary-adrenal axis in obese women with different patterns of body fat distribution J Clin Endocrinol Metab 1993; 77: 341—346 Andrew R, Phillips DIW, Walker BR Obesity and gender influence cortisol secretion and metabolism in man J Clin Endocrinol Metab 1998; 83: 1806—1809 Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JMC Cortisol effects on body mass, blood pressure, and cholesterol in the general population Hypertension 1999; 33: 1364—1368 Hautanen A, Adlercreutz H Altered adrenocorticotropin and cortisol secretion in abdominal obesity: implications for the insulin resistance syndrome J Intern Med 1993; 234: 461—469 Ljung T, Andersson B, Bengtsson B, Bjorntorp P, Marin P Inhibition of cortisol secretion by dexamethasone in relation to body fat distribution: a dose-response study Obes Res 1996; 4: 277—282 Walker BR, Soderberg S, Lindahl B, Olsson T Independent effects of obesity and cortisol in predicting cardiovascular risk factors in men and women J Intern Med 2000; 247: 198—204 Rosmond R, Dallman MF, Bjorntorp P Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and haemodynamic abnormalities J Clin Endocrinol Metab 1998; 83: 1853—1859 Phillips DIW, Barker DJP, Fall CHD, Whorwood CB, 292 INTERNATIONAL TEXTBOOK OF OBESITY partum period (50,55,76,77) A large proportion of new mothers stay at home for a time after birth, and whilst at home they often have greater access to food throughout more of the day than they had before they were pregnant (65,66) Among mothers participating in the Stockholm Pregnancy and Weight Development Study, those who displayed less well-structured eating patterns retained more weight by year postpartum (55) Women who increased in body weight also reported that their energy intake had risen during pregnancy and the postpartum period because they ate larger portions and snacked more frequently These women also skipped breakfast and lunch more regularly than women who put on less weight (55) In a descriptive study by Harris et al (65), more than 70% of mothers felt they ate differently from the way they did before they were pregnant Mothers who felt they ate more after their children were born displayed significantly greater long-term weight gains (2.78 kg) than those who felt they had not increased the amount they ate ( 1.15 kg) Although this association just failed to reach significance after accounting for the effects of confounding factors (P : 0.08; (68), this finding may be important since more than a fifth of the mothers in the group reported increasing their energy intake after the birth of their child In this study, more than 13% of the mothers who reported increasing their energy intake were newly classified as overweight or obese (BMI 26.0) after pregnancy (68) Mothers often report having to grab their meals when they can, and devoting more time to feeding their children than they to preparing food for themselves (65) It is therefore possible that these changes in maternal eating habits and patterns of eating predispose some women to gain weight after pregnancy It is important that women are aware of this possibility, so they can take steps to prevent these new behaviours from tracking into the future Dieting and Attitudes to Weight Gain Studies show that between 13 and 52% of European women undertake some form of dieting during the first year after birth (54,65) There is, however, little evidence to suggest that these women are any more successful in returning to their pre-pregnant weight than are those who not diet during the postpartum period (65) For some women, a previous history of dieting has been shown to be positive- ly related to pregnancy-related weight gain (54) but this is not the case for all women (65) It is likely that the impact of dieting on body weight is just as difficult to predict after pregnancy as it is at any time in a woman’s life, although some believe the immediate post-pregnancy period to be a betterthan-average time to achieve a successful persistent weight loss (16,78,79) Some women do, however, appear to experience marked changes in their attitudes to weight gain both during and after pregnancy For woman who normally restrain their eating to preserve their figures, the inevitable change of shape during pregnancy may serve as justification for ‘letting themselves go’ Others believe they should ‘eat for two’ or fear that by depriving themselves they are depriving their child In a recent UK study more than 40% of mothers felt it was inevitable that they retained some of the weight that they gained during pregnancy (65) In this study changes in attitude to weight gain were also assessed using the ‘drive for thinness’ sub-scale of the Eating Disorder Inventory (80) This scale contains seven questions that assess ‘concern with dieting, preoccupation with weight, and entrenchment in an extreme pursuit of thinness’ Harris et al (65) showed that mothers displayed significantly greater scores in their drive for thinness after pregnancy than they did before (P : 0.001) Interestingly, those mothers with an increased drive for thinness had not gained significantly more weight than those mothers who displayed no increase in drive for thinness after pregnancy Such changes in attitudes to weight gain, which are independent of actual changes in body weight, are suggestive of an increased vulnerability to eating psychopathology during the postpartum period (81) For these women, pregnancy may represent an important ‘risk period’ for the development of obesity Change of Body Image In Western society, the notion of beauty in women equates with being thin (82), and it is therefore not surprising that women are commonly concerned about their weight and shape both during and after pregnancy Younger or primiparous women can be somewhat unrealistic in forecasting their expected postnatal weight, and the greater the difference between anticipated and actual postnatal weight, the greater the postnatal weight dissatisfaction (83) This may be important as others have found that, Pregnancy after accounting for the effects of potential confounders and known risk factors for maternal obesity, women who were more dissatisfied with their bodies after pregnancy were significantly more likely to have higher long-term weight gains than those who displayed no increase in dissatisfaction with their bodies after pregnancy (P : 0.01; (68)) This association suggests that either (i) increased body image dissatisfaction predisposes mothers to gain more weight in association with pregnancy or (ii) mothers who gain more weight following pregnancy are more dissatisfied with their bodies Bivariate correlation analyses have shown mothers who were more dissatisfied with their bodies postpartum to be more likely to report an increase in energy intake following pregnancy While it is impossible to determine the causal direction of these relationships, previous analyses have demonstrated significantly higher levels of depression among women with increased body dissatisfaction following pregnancy (68) The changes in body image that occur following pregnancy might therefore lead to depression and reduced self-esteem, which in themselves are known risk factors for increased energy intake (84), particularly among women (85,86) Risk Factors Associated with the Postpartum Period Breast-feeding Breast-feeding has traditionally been thought to facilitate weight loss In clinical practice, women are often instructed to try to breast-feed as much as possible to revert to normal weight after delivery (72) This seems logical since a full lactation requires about 500 kcal a day, which for many women in this age group may constitute around 20 to 25% of their daily energy requirement (72) In theory, the metabolic costs of lactation can be met in four main ways: women can either (1) increase their energy intake, (2) mobilize their energy stores, (3) increase their metabolic efficiency, (4) reduce their energy expenditure, or employ a combination of these four adaptations From a nutritional point of view, it seems reasonable to assume that the adipose tissue that is stored during pregnancy provides energy for the child during the lactation period However, it is evident from the literature that postpartum weight changes in breast-feeding women are highly vari- 293 able both within and across populations (87) Several studies have supported a positive influence of breast-feeding on weight loss (62,88,89), while others have shown a negative influence (26,46,90) or little influence at all (50,56,58,60,63,69,90—92) Overall, breast-feeding appears to have its greatest effect in the early months (54,62,87,89,91,93), yet by 12 months postpartum (after which time most women have stopped breast-feeding) the difference in weight loss between those who had been breast-feeding and those who had not is minimal (54,92,93) Only in the small numbers of women who breast-feed for lengthy periods (around 12 months), does breast-feeding appear to be related to increased weight loss (54,93) In the Stockholm Pregnancy and Weight Development Study, Ohlin and Rossner (54) found ă breast-feeding to have only a minor influence on postpartum weight development: In this study a scoring system was constructed to reflect both the duration and intensity of breast-feeding Their system gave every month of full lactation a score of points, and every month with mixed feeding a score of points This score was then multiplied by the number of months during which women indicated that they breast-fed This system made it possible to sum up periods of complete lactation with ensuing periods of partial lactation, and in this way a range from 10 to 48 points was obtained to give a rough estimate of the total energy expenditure for milk production Although they found a significant relationship between lactation score and weight retention, the relationship was very weak (r : 0.09, P : 0.01) However, they were able to demonstrate that women with high lactation scores lost more weight during the first months following delivery, but by the end of the year the difference between the groups was limited (Figure 20.6) Insensitive definitions which fail to reflect the duration and intensity of breast-feeding are inevitably responsible for some of the conflicting results on the influence of breast-feeding on body weight Likewise the paucity of data on energy intakes makes interpretation and inter-study comparisons difficult Nevertheless, in most reports, rates of weight loss not differ between breast-feeding and non-breast-feeding women, and only subtle shortterm differences in body composition are observed following pregnancy (87) In those studies that demonstrate a statistically significant effect of breastfeeding on body weight, the contribution to the 294 INTERNATIONAL TEXTBOOK OF OBESITY body weight are sufficiently limited to warrant minimal emphasis on breast-feeding as a means of minimizing postpartum weight retention Psychosocial Factors: Depression, Self-esteem, Stress and Social Support Figure 20.6 Weight loss (kg) from 2.5 months postpartum in groups with different lactation scores * Differed from 0—9, 10—19 (P : 0.05) ** Differed from 0—9, 10—19 (P : 0.01) From Ohlin and Rossner (54) Reproduced by permission of MacMillan ă Press Ltd overall variability in postpartum weight change is minor (87) In developed countries, it seems that changes in eating behaviour and lifestyle affect women in such a way that they use their adipose tissue storage only when food is not readily available For example, several studies (94,95) indicate that well-nourished women with foods freely available not necessarily mobilize body fat during lactation, but rather tend to cover the energy costs of lactation by an increased energy intake and possibly by decreased physical activity (96) In this way changes in eating behaviour patterns after delivery seem to counteract the inherent weight controlling potential of breast-feeding This behaviour may go some way to explain why women from developed countries tend towards obesity following pregnancy, while women in developing countries tend towards maternal depletion In developed countries, it is likely that the effects of breast-feeding on There are a number of other psychosocial factors, such as depression, self-esteem, stress and social support, that might also influence maternal energy balance after pregnancy These risk factors have received relatively little attention and are notoriously difficult to measure As such, absence of an association between any of these variables and weight gain does not always mean that no association exists These factors rarely operate in isolation and usually form part of a complex milieu of social and emotional factors that make up a woman’s life Even when psychosocial variables, like these, are found to be related to a biological outcome, like body weight, questions necessarily arise about the processes that underlie the relationships If data on psychosocial symptoms and postpartum weight are collected simultaneously, the direction of influence of any relationship is usually unclear For example, women may experience depressive symptoms as a result of their weight or depressive symptoms may modify biological or behavioural processes that affect body weight Therefore, the direction of these causal relationships is usually difficult to predict and most studies are only able to describe tentative associations between psychosocial variables and body weight For these and other reasons, studies investigating the influence of psychosocial factors on body weight are scarce Some researchers have investigated the effects of stress on changes in body weight following pregnancy (65,67) However, these studies have found no association between life event stress or the stresses of parenting and long-term weight gain following pregnancy (65,67) However, both Walker (67) and Harris et al (65) found high levels of stress and low levels of social support to be related to higher depressive symptoms, which in themselves have been shown to be related to long-term weight gain following pregnancy (67,83) Others have suggested that weight loss following delivery might depend upon the amount of social support each mother receives (97) and that women with little social support, who might feel isolated and lonely as a result, respond to their lack of support by compensatory Pregnancy ‘comfort’ eating There is tentative evidence to support this view (67,68), although the mechanisms that underlie this association are far from clear Other researchers have explored the effects of changes in self-esteem following pregnancy Given the importance of body weight to perceived attractiveness, and the importance of attractiveness to a women’s self-image (82), it follows that a woman’s satisfaction with her weight is likely to be a central aspect of her self-esteem In a study by Walker (67), mothers were asked at year postpartum whether their current body weight affected how they felt about themselves, and just less than half of the entire sample (47%) reported that their self-esteem had decreased Reduced self-esteem and the normally inescapable demands imposed by motherhood can set the stage for depressive symptoms during the period after childbirth (67) In fact in Walker’s study (67), those mothers with gains at year postpartum of at least kg reported high depressive symptoms more often than women with lesser gains (53% vs 28%) It is likely that psychosocial factors play an important role in the development of maternal body weight following pregnancy However, well-designed prospective studies are needed if the effects of these factors are to be elucidated Pre-existing Risk Factors Pre-pregnant Weight Along with gestational weight gain, pre-pregnancy weight is the other variable that consistently shows a significant positive association with pregnancyrelated weight gain (19,49,50,56,58) This suggests that women who enter pregnancy with an already high body weight are at greater risk of long-term weight gain than are women of lower body weight Furthermore, the weight development of women who begin pregnancy overweight is known to be more variable (52,54,57,66) For example, Keppel and Taffel (57) showed that among normal weight women (BMI 19.8—26.0 kg/m) whose gestational gains were within the Institute of Medicine’s recommended range (see Table 20.3), 20% retained kg or more, while 29% lost weight by 10—18 months postpartum In contrast, of the overweight women (BMI 26.1—29.0 kg/m) who gained as recommended, 38% retained kg or more, while 33% lost weight 295 This variability of pregnancy-related weight gains is a remarkably consistent feature of postpartum weight change in overweight women To some extent, the higher weight gains of heavier mothers may be the result of fundamental differences in physiology and/or lifestyle that place these women at increased risk of gaining more weight, irrespective of pregnancy Differences in nutritional status (BMI) are the consequence of differences in physiological characteristics and/or lifestyles that cause some women to gain more weight than others There are, however, two important points to consider Firstly, overweight women are known to under-report their body weight to a greater extent than women of lower weight (18,19) Because weight retention is usually calculated as: body weight measured after pregnancy minus prepregnant weight, overweight women may appear to be retaining more weight than lighter women with the same weight retention, when calculations are based on self-reported pre-pregnant weight (50,58) This does not, however, explain the greater weight gains observed among overweight women in studies that rely on pre-pregnant body weights that are measured in early pregnancy (50,56) Secondly, the increased risk of weight retention observed among overweight women might simply be an artefact of longitudinal study design: for example, we might observe this relationship simply because heavier women gain more weight over a fixed period of time than lighter women, regardless of pregnancy This would give the impression that overweight women are at greater risk of pregnancy-related weight gains, when in fact they are simply at greater risk of weight gain generally (98) With this in mind, there is little empirical evidence to suggest that overweight women are at any increased risk of maternal obesity when compared to women of lower body weight (98) Heredity Few studies have considered the effects of heredity on postpartum weight, and this represents an important oversight since heredity is considered to be one of the three most important factors determining body weight (99) More than 50 years ago clinicians noticed that mothers of the maternal obese had more often suffered from obesity after pregnancy than had mothers of women whose obesity was not pregnancy-related (14,100) These early observa- 296 INTERNATIONAL TEXTBOOK OF OBESITY tions suggested that a history of maternal obesity in a woman’s mother might be a risk factor for pregnancy-related weight gain Harris et al (68) assessed the relative importance of heritable characteristics and lifestyle in the development of body weight following pregnancy in a group of mothers from south-east London In this study, 74 mothers of low antenatal risk who had been weighed during the first trimester of pregnancy were followed up 2.5 years after delivery ‘Heritable’ predisposition to gain weight was assessed using the Silhouette Technique (101) This technique asks subjects to score the degree of obesity in their parents using a series of nine silhouette drawings showing bodies of increasing obesity, ranging from very thin to very obese (numbered in order from to 9) This technique has been validated by correlation with BMI, as offspring’s selected silhouettes of their mothers have been shown to correlate well with measured maternal BMI (r : 0.74: Sørenson and Stunkard (101)) After adjusting for the effects of potential confounders and known risk factors for maternal obesity, women who selected larger silhouettes to represent their biological mothers were significantly more likely to have higher long-term weight gains than those who selected thinner maternal silhouettes (r : 0.083, P : 0.004; see Figure 20.7) Interestingly, long-term weight gain was not associated with the size of the biological father (P : 0.50) This shows that a ‘heritable’ predisposition to gain weight is independently associated with long-term weight gain following pregnancy, and suggests that some component of heredity might determine why some women gain more weight than others in association with pregnancy A number of previous studies have shown that the familial resemblance of obesity has a genetic component which may be inherited (101—104), with twin and adoption studies indicating that genes play a major role (102) However, it is also possible that offspring ‘inherit’ lifestyles that predispose them to gain weight by adopting similar eating habits and exercise patterns to those of their parents The absence of an association between long-term maternal weight gain and the size of the biological father (68) suggests that inherited maternal attitudes to body weight and weight gain, as well as postpartum lifestyle, might be more important than any genetic characteristic inherited from either parent Nevertheless, it is likely that both processes have a role Figure 20.7 Mean long-term weight gains of 74 women according to the number of silhouette selected to represent their biological mother Error bars show standard error about the mean and sample size is shown in parentheses From Harris et al (68) Reproduced with permission of the BMJ Publishing Group Maternal Age The results of studies on the modification of pregnancy-related weight gain by age are limited and conflicting Some show no significant association between maternal age and weight gain following pregnancy (49,50,70), while others show a significant negative influence (54,62,63) Another recent study showed that among white women, younger compared to older women were found to be more likely to experience substantial pregnancy-related weight gains (defined as gains 11.4 kg during the 10-year study period), while among black women, the opposite was true (105) It seems logical to assume that older women might be at greater risk of pregnancy-related weight gain, as a direct consequence of the reduced metabolic efficiency that accompanies advancing age Older mothers may also be less concerned about slimness than younger women (63) Janney et al (62) showed that age rather than parity influenced the rate of postpartum weight retention after a first or second pregnancy In this study, older women were shown to be significantly less likely to return to their pre-pregnant weight than younger women They also had slower rates of weight loss than their younger counterparts The significant interaction between maternal age and time since delivery is illustrated in Figure 20.8 (62) This model suggests that for women who experience pregnancy between the ages of 20 and 35 years, regaining pre-pregnant weight would be anticipated, but for women who Pregnancy Figure 20.8 Predicted weight retention curves for women of various ages (hypothetical married women who fully breast-fed for months and gained 15.9 kg during pregnancy) , 40 years; s, 35 years; , 30 years; u, 25 years From Janney et al (62) Reproduced by permission of the American Society for Nutritional Sciences experience pregnancy between the ages of 35 and 40 years, an average weight retention of up to kg is predicted by 18 months postpartum Ohlin and Rossner (54) also reported age to be more strongly ă related to long-term weight gain (P : 0.05) than was parity, and among primiparous women, those in the oldest age group ( P 36 years) retained significantly more weight (2.9 kg) than did younger women (1.4 kg) Given the current trend toward delayed childbearing (106), the risk of weight retention among mothers over the age of 35 certainly warrants further examination Parity The interaction between parity and body weight is complex and highly confounded with maternal age because older women tend to have more children than younger women (25) After accounting for differences in maternal age, an effect of parity on body weight is only consistently observed at high parities (28,52,70) Harris et al (70) investigated the independent relationship between parity and maternal weight gain in a group of 523 multiparous women from south-east London In this repeat-pregnancy study, the change in maternal body weight from the beginning of one pregnancy to the beginning of the next was examined, and parity was found to be indepen- 297 Figure 20.9 Independent relationships between weight gain and parity (data from Harris et al (70) Adjusted for the effects of smoking status, alcohol consumption, socioeconomic status, breast-feeding at hospital, maternal age, nulliparous BMI, marital status, birth weight, plus (for analyses of inter-pregnancy weight gain only) gestational weight gain, and inter-pregnancy interval dently associated with both gestational weight gain and inter-pregnancy weight gain (Figure 20.9) These relationships suggest that first-time mothers are at risk of long-term weight gain because they gain the most weight during pregnancy, and high gestational weight gain is in itself a risk factor for long-term weight gain (49,50,57) However, women of higher parity (4 ; ) seemed to be at risk of longterm weight gain because they gained more weight in association with pregnancy, irrespective of the amount of weight they gained during pregnancy Therefore, for women of parity or less, the association between maternal body weight and parity appeared to be the result of cumulative weight gains during successive pregnancies For women of higher parity, the association between maternal body weight and parity was partly the cumulative effect of excess gestational weight gains from successive pregnancies, and partly the result of gaining more weight in association with later pregnancies It could be that the increase in weight gain observed with increasing parity is the result of women of higher parity having their pregnancies at older ages ‘when weight gain is the norm’ (66) However, more sophisticated analyses have shown the effects of parity on body weight to be independent of maternal age (28,70) Alternatively, mothers of high parity might gain more weight in association with pregnancy as a result of differential effects of motherhood at different parities For example, 298 INTERNATIONAL TEXTBOOK OF OBESITY Dodge and Silva (107) showed that the pressures of child rearing increased with family size In their study, the numbers of symptoms reported by mothers concerning physical ill health (including changes in body weight) were found to be positively correlated with the number of children living at home Similarly, the numbers of symptoms concerning psychological ill health (including anxiety and depression) were significantly correlated with the number of children at home, especially in mothers with children of pre-school age Since many women respond to stress by increasing their energy intake (85,86), this might explain why mothers with larger families tend to gain more weight than mothers with fewer children It is also conceivable that different demographic groups, who are at greater risk of weight gain, are selected into this high parity group and that the observed association is simply the result of uncontrolled confounding The variable success of investigators to control for the effects of socioeconomic status might therefore explain why other researchers have found no effect of parity on weight development after pregnancy (49,54,60) Ethnicity To date, the relationship between ethnicity and maternal body weight has largely been restricted to a few national studies of white and black US women (48,57,69) These studies consistently show pregnancy-related weight gains to be greater in AfricanAmericans than in white women (105), and at any level of weight gain, black women are seen to retain more weight postpartum than white women (48,57,58,61,69) Data from the 1988 National Maternal and Infant Health Survey show that among women of normal BMI, black mothers are more than twice as likely than white mothers to retain at least kg postpartum (69) This difference was shown to persist after adjustment for differences in maternal age, parity, gestational weight gain, infant birth weight, height, BMI, marital status and social class The reasons for this differential impact of pregnancy on body weight among women from different ethnic backgrounds are not clear A possible explanation has been suggested by researchers who examined national data on energy intakes before, during and after pregnancy (108) In this study, the reported energy intakes of non-lactating white women ap- peared to decrease after pregnancy, whereas for black women, mean increases of more than 300 kcal over pre-pregnant intakes were reported by months postpartum This finding is consistent with others which suggest that black women are not necessarily at increased risk of gaining weight, but rather that they are less likely to lose it (58,109) Other studies have shown that factors related to postpartum weight retention differ by ethnic group: For example, married white mothers appear to have a lower risk of excess weight retention than unmarried white mothers, but among black mothers, marital status was unrelated to weight retention (69) In a similar way, high parity predicted retained weight for black but not white mothers (69) These and other observations suggest that ethnicity is probably just a proxy for social, economic, environmental, cultural and other factors that influence a woman’s body weight following pregnancy Marital Status, Education, Income and Socioeconomic Status Greater weight retention has been observed among unmarried women when compared to married women (49,62,68,69) Janney et al (62) showed that unlike married women, unmarried women had a pattern of weight gain rather than weight loss, and Harris et al (70), in their study of 523 multiparous English women, also showed marital status to be significantly related to long-term weight gain After adjusting for the influence of confounding factors, Harris et al (70) found that unmarried mothers retained significantly more weight (4.0 kg) than married mothers (3.15 kg) by at least year postpartum In this context it is likely that marital status serves as a proxy for socioeconomic status and/or social support However, others have found no effect of marital status on long-term weight gain following pregnancy (54) Marital status is just one of many component measures of socioeconomic status, and the relationships between the various measures of socioeconomic status and pregnancy-related weight gain are complex and inconsistent Most studies show women with lower incomes or less education to be at increased risk of retaining weight postpartum (61,67,69,90) However, others that have measured socioeconomic status by occupation or social class have found no significant associations (49,50,54,70) As with many health outcomes, it is Pregnancy likely that the poorest members of society will be at greatest risk of maternal obesity PREVENTION AND TREATMENT OF MATERNAL OBESITY It is often said that ‘prevention is better than cure’, but in the context of pregnancy, this cannot be taken as read Because excessive gestational weight gain is probably the most important risk factor for maternal obesity, restricting the amount of weight that women gain should theoretically help to reduce the burden of obesity-related disease in women However, restricting weight gain during pregnancy presents health care workers with a dilemma: weight restriction may help to diminish the risk of maternal obesity, but may also affect the development of the growing child In any event, advocating weight restriction during pregnancy may be a moot point, because there is little empirical evidence to suggest that weight gain is easy to modify during pregnancy (110) Mothers routinely report difficulties in complying with dietary instructions during pregnancy (111,112) because they usually experience a ‘surge of appetite’ during pregnancy (113) which is difficult to overcome (Dieckmann 1952 in Hytten (113)) Even if it were possible or beneficial to modify the amount of weight women gain during pregnancy to reduce the prevalence of maternal obesity, the association between fetal development in utero and health later on in life (114—117) should make clinicians extremely cautious when recommending weight restriction during pregnancy, even for those mothers whose gains appear excessive Restricting weight gain during pregnancy may have undesirable consequences not only for the fetus, but for the generations that follow as the effects of inadequate biological development in utero can establish the biological parameters within which individuals will function later in life (115,117) For these reasons, it would seem more appropriate to address the problem of pregnancy-related weight gains soon after the birth, at a time when fetal growth cannot be compromised At this time it would also be appropriate to forewarn mothers of the changes in lifestyle that accompany motherhood which can encourage further weight gain During the postpartum period women are offered 299 little advice (66) Many are only likely to see a physician for a 6-week check-up, and at this time women may be receptive to advice about their own health as they recognize their responsibility for a new life (66) In this setting, it could be made clear that permanent weight gain need not be a consequence of pregnancy, and that lifestyle changes rather than biological changes may be a more important cause of pregnancy-related weight gains (66) Helping mothers to establish appropriate exercise routines should be an important component of postpartum care In recent years, exercise has been shown to be beneficial to health, and postpartum women are no exception (106) Unfortunately there are many barriers to regular exercise for a mother with a new baby, and perhaps other young children at home The cost of child care and formal exercise often makes these pursuits prohibitive, and for many there are difficulties in accessing leisure facilities (65) Likewise, lack of time, particularly for working mothers, often makes participation in exercise difficult following pregnancy (65) Even walking can jeopardize personal safety and cause fear among mothers who live in areas of high crime (106) Consequently, health care providers should discuss exercise needs individually and set realistic goals that are tailed to the individual’s needs (106) Women should be given realistic advice about postpartum weight change as well as assistance in beginning or maintaining lifestyles that will promote health and an appropriate body weight For some new mothers, dealing with the demands of an infant, running a household, and in many cases holding a job as well, make dieting and other weight loss strategies seem overwhelming (61) Health care providers should therefore have a supportive attitude to ensure that concerns about weight management are balanced with concerns about maternal self-esteem The following five recommendations should go some way to reduce the burden of disease associated with maternal obesity: ∑ Women should be encouraged to eat to appetite during pregnancy by consuming a varied and balanced diet, but be advised that it is not necessary to ‘eat for two’ in order to provide the appropriate nutrients for their growing child ∑ Mothers should be given assistance in beginning or maintaining lifestyles that will promote health and an appropriate body weight at the time of 300 INTERNATIONAL TEXTBOOK OF OBESITY their 6-week postpartum check-up ∑ Mothers should be forewarned of the changes in eating habits that often accompany pregnancy and motherhood which predispose weight gain so they can take steps to prevent these new behaviours from tracking into the future ∑ Mothers should be encouraged to maintain or establish appropriate exercise 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Midwifery 1990; 6: 28—32 114 Barker DJP, Bull AR, Osmond C, Simmonds SJ Fetal and placental size and risk of hypertension in adult life BMJ 1990; 301: 259—262 115 Barker DJP, Godfrey KM, Osmond C, Bull A The relation of fetal length, ponderal index and head circumference to blood pressure and the risk of hypertension later in life Paediatr Perin Epidemiol 1992; 6: 35—44 116 Law CM, Barker DJP, Osmond C, Fall CHD, Simmonds SJ Early growth and abdominal fatness in adult life In: Pregnancy Barker DJP (ed.) Fetal and Infant Origins of Adult Disease London: British Medical Journal Publications, 1992: 291—296 117 Wadsworth MEJ, Kuh DJL Childhood influences on adult 303 health: A review of recent work from the British 1946 national birth cohort study, the MRC National survey of Health and Development Paediatr Perin Epidemiol 1997; 11: 2—20 International Textbook of Obesity Edited by Per Bjorntorp Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic) 21 Social and Cultural Influences on Obesity Jeffery Sobal Cornell University, Ithaca, New York, USA INTRODUCTION Obesity may be defined as the condition of having high levels of stored body fat Relative body weight is commonly used to describe obesity, and people who are obese are commonly described as being overweight Obesity and overweight are complex biopsychosocial phenomena that are shaped by many factors, including a variety of social and cultural influences This chapter will examine patterns of fatness and thinness using social science perspectives to frame, review, and discuss social and cultural influences on obesity Framing the influences on obesity first involves examining the larger social contexts of culture and history, and then considering the more specific social characteristics of individuals Societal mechanisms involved in energy intake and energy expenditure will be discussed in light of their collective contribution to rising levels of body weight Finally, conclusions about the social aspects of weight will be presented SOCIAL CONTEXTS Two major social contexts provide overarching perspectives for framing obesity: culture and history The culture within which a person lives is likely to be the most powerful influence on their eating patterns, activity levels, and body weight Within each International Textbook of Obesity Edited by Per Bjorntorp ă â 2001 John Wiley & Sons, Ltd culture, conditions change (sometimes dramatically) over time, and historical period is also a strong influence on levels of fatness and thinness of individuals and populations Culture Culture is the learned system of categories, rules, and plans that people use to guide their behaviors (1,2) A person’s culture permeates every aspect of their life, including how they think about fatness and thinness, eating behaviors, activity patterns, and all other facets of living in the world Cultural values and norms about body weight vary considerably Anthropologists estimate that there have been fewer than 8000 cultures that have existed in the world (3), although we only have information about a minority of all cultures that have existed Information about body weight levels and weight beliefs is not available for the vast majority of cultures Archaeological evidence about body weight is rare because body fat tissue is not well preserved over long periods of time Ancient representations of human figures such as drawings and sculptures provide some information about weight beliefs or ideals, but not necessarily actual weight patterns or fatness norms The 25 000year-old Venus of Willendorf is a tiny female statuette with a huge stomach and large, pendulous breasts that is often suggested to be a maternal or 306 INTERNATIONAL TEXTBOOK OF OBESITY fertility icon, and is an artifact widely discussed as evidence about past cultural preferences for plump body shapes for women (4) However, this figure is not necessarily representative of all icons of the same era because that period is unique and the place it originated from is dissimilar from other ancient cultures (5) Holocultural analyses examine large samples of cultures (1), but few such investigations have examined perceptions about body weight Brown and Konner (6) found that information about weight ideals was not available for most cultures, although among the 38 cultures that had data about female shape ideals, 81% (31) preferred plumpness or moderate fat rather than thinness or extreme obesity Anderson et al (7) also examined cross-cultural data and also found that 81% (50 of 62 cultures for which data was available) preferred fatter individuals Ritenbaugh (8) suggests that the condition of obesity and the rejection of fatness may be a culture-bound phenomenon (9), meaning that it is particular to contemporary postindustrial societies and not culturally recognized by other societies Overall, cross-cultural analyses suggest that most cultures in the world have valued moderate fatness and avoided extreme thinness People who live in economically developed societies are more likely to be obese than their counterparts in developing societies (10) Modernization is the complex set of social changes that occur as societies shift from being ‘traditional’ to ‘modern’ (11) Modernization involves shifts in modes of economic production for whole societies, which has substantial impacts on energy expenditure of human populations Primary production extracts raw materials from the environment in agriculture, hunting and fishing, gathering, timbering, etc., and traditionally drew energy largely from muscles of humans and animals Secondary production transforms raw materials into manufactured products, and on a mass scale typically draws energy from fossil, hydrological, or other fuels Tertiary production provides services to consumers, and is not as dependent on physical energy sources as primary and secondary production As whole societies shift from being based on primary to secondary to tertiary production as they modernize, the energy expenditure of most people in the population decreases dramatically Examples from across the globe reveal that people are becoming fatter in modernizing societies (12,13) Comparisons between various contemporary developed societies reveal substantial differences in body weight (14—16) that may be associated with modernization but also reflect cultural differences For example, cultural differences between the USA and France in values about food and body weight have strongly shaped the prevalence of obesity in those two cultures (17) Cultural predispositions to obesity exist, with life in contemporary postindustrial cultures more likely to lead members of those cultures to become obese (5) Migration between cultures places people into new food systems and new social and built environments, and has important health consequences (18) Zelensky (19) proposed that a migration transition is occurring, where people are travelling and moving more frequently and over longer distances While migration flows occur between most areas of the world, the major migration streams tend to move from less developed to more developed societies People in these dominant migration streams tend to gain weight after migration (20) The loss of the buffering effects of the traditional culture of many migrants puts them at further risk of illness if they gain weight in a new society (21) Specific mechanisms for relationships between migration and weight vary, with the relative contribution of energy intake and energy expenditure being specific to the circumstances of particular individuals and groups coming from distinctive origins to unique destinations Also, the relative contributions of selection versus causation (22) are not clearly understood for migration, with a need for further investigation of the extent that migrants have a differential predisposition for weight change or whether the new environments of immigrants changes their weights Acculturation occurs as people become socialized into another culture (23,24) Acculturation is a multidimensional phenomenon, and can operate differently for various domains such as social relationships, behaviors, values, and other topics (25) Studies in the USA suggest that acculturation is associated with increases in body weight (26,27) The relationship between relative body weight and acculturation often varies among particular ethnic subgroups, with US Hispanic migrant groups having acculturation more strongly associated with weight for Mexican Americans and less for Cuban Americans and Puerto Ricans (20) Overall, culture and the dynamics of culture ... of 154 155 1 56 157 158 159 160 161 162 163 164 165 166 167 168 169 265 steroid -reductase isozymes Proc Endocr Soc 1998; 80: OR5 0-1 (Abstract) Davis EA, Morris DJ Medicinal uses of licorice through... Keppel KG, Taffel SM Pregnancy-related weight gain and 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 301 retention: Implications of the 1990 Institute of Medicine Guidelines Am J Public... 1999; 53: 230—232 56 Horton R, Rothwell NJ, Stock MJ Chronic inhibition of 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 279 Gaba Transaminase results in activation of thermogenesis and