Does oestrogen allow women to store fat more efficiently? A biological advantage for fertility and gestation: Etiology and Pathophysiology

Obesity Reviews

Volumn 10, Issue 2, 2009, Pages 168-177

  O'Sullivan, A J ^a,b  

^a ST GEORGE HOSPITAL   (Australia)

^b UNIVERSITY OF NEW SOUTH WALES   (Australia)

Author keywords

Adipose tissue; Body composition; Fatty acid oxidation; Oestrogen

Indexed keywords

ANDROGEN; ESTROGEN; PRASTERONE; TESTOSTERONE;

ADIPOSE TISSUE; BASAL METABOLIC RATE; BODY FAT; FATTY ACID OXIDATION; FEMALE; FEMALE FERTILITY; FETUS DEVELOPMENT; HUMAN; LIPID STORAGE; POSTPRANDIAL STATE; PREGNANCY; REVIEW; SEX DIFFERENCE;

ADIPOSE TISSUE; ESTROGENS; FATTY ACIDS; FEMALE; HUMANS; LIPID METABOLISM; MALE; OXIDATION-REDUCTION; POSTPRANDIAL PERIOD; PREGNANCY;

EID: 61349100167     PISSN: 14677881     EISSN: 1467789X     Source Type: Journal    
DOI: 10.1111/j.1467-789X.2008.00539.x     Document Type: Review

References (109)

1. Hill JO. Understanding and addressing the epidemic of obesity: an energy balance perspective. Endocr Rev 2006 27 : 750 761.
2. Rosenbaum M, Leibel RL. Role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin. J Clin Endocrinol Metab 1999 84 : 1784 1789.
3. Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 2007 9 : 282 289.
4. Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem 2004 50 : 1511 1525.
5. Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obes Rev 2007 8 : 515 523.
6. Zafon C. Oscillations in total body fat content through life: an evolutionary perspective. Obes Rev 2007 8 : 525 530.
7. Bouchard C, Despres J-P, Mauriege P. Genetic and nongenetic determinants of regional fat distribution. Endocr Rev 1993 14 : 72 93.
8. Meinhardt UJ, Ho KKY. Modulation of growth hormone action by sex steroids. Clin Endocrinol 2006 65 : 413 422.
9. Leung KC, Johannsson G, Leong GM, Ho KKY. Estrogen regulation of growth hormone action. Endoc Rev 2004 25 : 693 721.
10. Aiello LC, Key C. Energetic consequences of being a homo erectus female. Am J Hum Biol 2002 14 : 551 565.
11. Hill JW, Elmquist JK, Elias CF. Hypothalamic pathways linking energy balance and reproduction. Am J Physiol 2008 294 : E827 E832.
12. Jeffrey RW, Harnack LJ. Evidence implicating eating as a primary driver for the obesity epidemic. Diabetes 2007 56 : 2673 2676.
13. Swinburn B, Ravussin E. Energy balance or fat balance? Am J Clin Nutr 1993 57 (Suppl. 766S 71S.
14. Durnin JVGA, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged 16 to 72 years. Br J Nutr 1974 32 : 77 97.
15. Forbes GB. Human Body Composition. Growth, Aging, Nutrition, and Activity. Springer-Verlag : New York, 1987.
16. Veldhuis JD, Roemmich JN, Richmond EJ, Rogol AD, Lovejoy JC, Sheffield-Moore M, Mauras N, Bowers CY. Endocrine control of body composition in infancy, childhood and puberty. Endocr Rev 2005 26 : 114 146.
17. Tanner JM, Whitehouse RH. Standards for subcutaneous fat in British children. Br Med J 1962 1 : 446 450.
18. Bitar A, Vernet J, Coudert J, Vermorel M. Longitudinal changes in body composition, physical capacities and energy expenditure in boys and girls during the onset of puberty. Eur J Nutr 2000 39 : 157 163.
19. Ogle GD, Allen JR, Humphries IR, Lu PW, Briody JN, Morley K, Howman-Giles R, Cowell CT. Body-composition assessment by dual-energy X-ray absorptiometry in subjects aged 4-26 year. Am J Clin Nutr 1995 61 : 746 753.
20. Horlick MB, Rosenbaum M, Nicolson M, Levine LS, Fedun B, Wang J, Pierson RN, Leibel RL. Effect of puberty on the relationship between circulating leptin and body composition. J Clin Endocrinol Metab 2000 85 : 2509 2518.
21. Nindl BC, Scoville CR, Sheehan KM, Leone CD, Mello RP. Gender differences in regional body composition and somatotrophic influences on IGF-I and leptin. J Appl Physiol 2002 92 : 1611 1618.
22. Chumlea WC, Guo SS, Kuczmarski RJ, Flegal KM, Johnson CL, Heymsfield SB, Lukaski HC, Friedl K, Hubbard VS. Body composition estimates from NHANES III bioelectrical impedance data. Int J Obes 2002 26 : 1596 1609.
23. Ashima KK, Graubard BI. Secular trends in patterns of self-reported food consumption of adult Americans: NHANES 1971-1975 to NHANES 1999-2002. Am J Clin Nutr 2006 84 : 1215 1223.
24. Pietrobelli A, Allison DB, Heshka S, Heo M, Wang ZM, Bertkau A, Laferrere B, Rosenbaum M, Aloia JF, Pi-Sunyer FX, Heymsfield SB. Sexual dimorphism in the energy content of weight change. Int J Obes 2002 26 : 1339 1348.
25. Aloia JF, Vaswani A, Ma R, Flaster E. Aging in women-the 4 compartment model of body composition. Metabolism 1996 45 : 43 48.
26. Australian Bureau of Statistics and Commonwealth Department of Health and Aged Care. National Nutrition Survey: Nutrient Intakes and Physical Measurements Australia 1995. Australian Bureau of Statistics : Canberra, 1998.
27. Cagnacci A, Zanin R, Cannoletta M, Generali M, Caretto S, Volpe A. Menopause, estrogens, progestins, or their combination on body weight and anthropometric measures. Fertil Steril 2007 88 : 1603 1608.
28. Giltay EJ, Gooren LJG. Effects of sex steroid deprivation/administration on hair growth and skin sebum production in transexual males and females. J Clin Endocrinol Metab 2000 85 : 2913 2921.
29. Elbers JMH, Ej G, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJG. Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Clin Endocrinol 2003 58 : 562 571.
30. Janssen I, Heymsfield SB, Allison DB, Kotler DP, Ross R. Body mass index and waist circumference independently contribute to the prediction of nonabdominal, abdominal subcutaneous, and visceral fat. Am J Clin Nutr 2002 75 : 683 688.
31. Blouin K, Boivin A, Tchernof A. Androgens and body fat distribution. J Steroid Biochem Mol Biol 2008 108 : 272 280.
32. Seidell JC, Bjorntorp L, Sjostrom H, Kvist R, Sannerstedt R. Visceral fat accummulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels. Metabolism 1990 39 : 897 901.
33. Synder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, Haddad G, Dlewati A, Santanna J, Loh J, Lenrow DA, Holmes JH, Kapoor SC, Atkinson LE. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000 85 : 2670 2677.
34. Wang C, Eyre DR, Clark R, Kleinberg D, Newman C, Iranmanesh A, Veldhuis JD, Dudley RE, Berman N, Davidson T, Barstow TJ, Sinow R, Alexander G, Swerdloff RS. Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men-a clinical research center study. J Clin Endocrinol Metab 1996 81 : 3654 3662.
35. Bhasin S, Storer TW, Berman N, Yarasheki KE, Clevenger B, Phillips J, Lee WP, Bunnell TJ, Casaburi R. Testosterone replacement increases fat-free mass and muscle size in hypogonadal men. J Clin Endocrinol Metab 1997 82 : 407 413.
36. Bhasin S, Tenover JS. Age-associated sarcopenia-Issues in the use of testosterone as an anabolic agent in older man. J Clin Endocrinol Metab 1997 82 : 1659 1660.
37. Nair KA, Rizza RA, O'Brien P, Dhatariya K, Short KR, Nehra A, Vittone JL, Klee GG, Basu A, Basu R, Cobelli C, Toffolo G, Dalla Man C, Tindall DJ, Melton LJ, Smith GE, Khosla S, Jensen MD. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2007 355 : 1647 1659.
38. Boyanov MA, Boneva Z, Christov VG. Testosterone supplementation in men with type 2 diabetes, visceral obesity and partial androgen deficiency. Aging Male 2003 6 : 1 7.
39. Katznelson L, Finkelstein JS, Schoenfeld DA, Rosenthal DI, Anderson EJ, Klibanski A. Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism. J Clin Endocrinol Metab 1996 81 : 4358 4365.
40. Woodhouse LJ, Gupta N, Bhasin M, Singh AB, Ross R, Phillips J, Bhasin S. Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young males. J Clin Endocrinol Metab 2004 89 : 718 726.
41. Bhasin S, Storer TW, Berman N, Callegari C, Clevenger B, Phillips J, Bunnell TJ, Tricker R, Shirazi A, Casburi R. The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men. N Engl J Med 1996 335 : 1 7.
42. Marin P, Oden B, Bjorntorp P. Assimilation and mobilization of triglycerides in subcutaneous abdominal and femoral adipose tissue in vivo in men: effects of androgens. J Clin Endocrinol Metab 1995 80 : 239 243.
43. Bhasin S. Regulation of body composition by androgens. J Endocrinol Invest 2003 26 : 814 822.
44. Kopp-Hoolihan LE, van Loan MD, Wong WW, King JC. Longitudinal assessment of energy balance in well-nourished, pregnant women. Am J Clin Nutr 1999 69 : 697 704.
45. O'Sullivan AJ, Martin A, Brown MA. Efficient fat storage in premenopausal women and in early pregnancy: a role for estrogen. J Clin Endocrinol Metab 2001 86 : 4951 4956.
46. Forsum E. Energy requirements during pregnancy: old questions and new findings. Am J Clin Nutr 2004 79 : 933 934.
47. Lof M, Olausson H, Bostrom K, Janerot-Sjoberg B, Sohlstrom A, Forsum E. Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones in relation to fetal growth. Am J Clin Nutr 2005 81 : 678 685.
48. Forsum E, Sadurskis A, Wager J. Resting metabolic rate and body composition of healthy Swedish women during pregnancy. Am J Clin Nutr 1988 47 : 942 947.
49. Van Loan MD, Kopp LE, King JC, Wong WW, Mayclin PL. Fluid changes during pregnancy: use of bioimpedance spectroscopy. J Appl Physiol 1995 78 : 1037 1042.
50. Butte NF, Wong WW, Treuth MS, Ellis KJ, O'Brian Smith E. Energy requirements during pregnancy based on total energy expenditure and energy deposition. Am J Clin Nutr 2004 79 : 1078 1087.
51. Lof M, Forsum E. Activity pattern and energy expenditure due to physical activity before and during pregnancy in healthy Swedish women. Br J Nutr 2006 95 : 296 302.
52. Kopp-Hoolihan LE, Van Loan MD, Wong WW, King JC. Fat mass deposition during pregnancy using a four-compartment model. J Appl Physiol 1999 87 : 196 202.
53. Durnin JV, McKillop FM, Grant S, Fitzgerald G. Is nutritional status endangered by virtually no extra intake during pregnancy? Lancet 1985 2 : 823 825.
54. van Raaij JM, Vermaat-Miedema SH, Schonk CM, Peek ME, Hautvast JG. Energy requirements in pregnancy in the Netherlands. Lancet 1987 2 : 953 955.
55. Prentice AM, Goldberg GR. Energy adaptations in human pregnancy: limits and long-term consequences. Am J Clin Nutr 2000 71 (Suppl. 1226S 32S.
56. Davidsen L, Vistisen B, Astrup A. Impact of the menstrual cycle on determinants of energy balance: a putative role in weight loss attempts. Int J Obes 2007 31 : 1777 1785.
57. Pansini F, Bonaccorsi G, Genovesi F, Folegatti R, Bagni B, Bergamini CM, Mollica G. Influence of estrogens on serum free fatty acid levels in women. J Clin Endocrinol Metab 1990 71 : 1387 1389.
58. Mayes JS, Watson GH. Direct effects of sex steroid hormones on adipose tissues and obesity. Obes Rev 2004 5 : 197 216.
59. Blaak E. Gender differences in fat metabolism. Curr Opin Clin Nutr Metab Care 2001 4 : 499 502.
60. Jensen MD. Gender differences in regional fatty acid metabolism before and after meal ingestion. J Clin Invest 1995 96 : 2297 2303.
61. Jacobs KA, Casazza GA, Suh SH, Horning MA, Brooks GA. Fatty acid reesterification but not oxidation is increased by oral contraceptive use in women. J Appl Physiol 2005 98 : 1720 1731.
62. Uranga AP, Levine J, Jensen M. Isotope tracer measures of meal fatty acid metabolism: reproducibility and effects of the menstrual cycle. Am J Physiol 2005 288 : E547 E555.
63. Pedersen SB, Bruun JM, Hube F, Kristensen K, Hauner H, Richelsen B. Demonstration of estrogen receptor subtypes alpha and beta in human adipose tissue: influences of adipose cell differentiation and fat depot localization. Mol Cell Endocrinol 2001 182 : 27 37.
64. Machinal F, Dieudonne MN, Leneveu MC, Pecquery R, Giudicelli Y. In vivo and in vitro ob gene expression and leptin secretion in rat adipocytes: evidence for a regional specific regulation by sex steroids. Endocrinology 1999 140 : 1567 1574.
65. Joyner JM, Hutley LJ, Cameron DP. Estrogen receptors in human preadipocytes. Endocrine 2001 15 : 225 230.
66. Pedersen SB, Kurt K, Hermann PA, Katzenellenbogen JA, Richelsen B. Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly in human adipose tissue through the estrogen receptor alpha. Implications for the female fat distribution. J Clin Endocrinol Metab 2004 89 : 1869 1878.
67. Palin SL, McTernan PG, Anderson LA, Sturdee DW, Barnett AH, Kumar S. 17Beta-estradiol and anti-estrogen ICI: compound 182780 regulate expression of lipoprotein lipase and hormone-sensitive lipase in isolated subcutaneous abdominal adipocytes. Metabolism 2003 52 : 383 388.
68. Roepstorff C, Donsmark M, Thiele M, Vistisen B, Stewart G, Vissing K, Schjerling P, Hardie DG, Galbo H, Kiens B. Sex differences in hormone-sensitive lipase expression, activity, phosphorylation in skeletal muscle at rest and during exercise. Am J Physiol 2006 291 : E1106 E1114.
69. Tikkanen MJ, Nikkila EA. Regulation of hepatic lipase and serum lipoproteins by sex steroids. Am Heart J 1987 113 : 562 566.
70. Walsh BW, Schiff I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991 325 : 1196 1204.
71. Deroo BJ, Korach KS. Estrogen receptors and human disease. J Clin Invest 2006 116 : 561 570.
72. Perseghin G, Scifo P, Pagliato E, Battezzati A, Benedini S, Soldini L, Testolin G, Del Maschio A, Luzi L. Gender factors affect fatty acids-induced insulin resistance in non-obese humans: Effects of oral steroidal contraception. J Clin Endocrinol Metab 2001 86 : 3188 3196.
73. O'Sullivan AJ, Crampton L, Freund J, Ho KKY. The route of oestrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women. J Clin Invest 1998 102 : 1035 1040.
74. O'Sullivan AJ, Hoffman DH, Ho KKY. Estrogen, lipid oxidation and body fat. N Engl J Med 1995 333 : 669 670.
75. Lwin R, Darnell B, Oster R, Lawrence J, Foster J, Azziz R, Gower BA. Effects of oral estrogen on substrate utilization in postmenopausal women. Fertil Steril 2008 90 : 1275 1278.
76. Gibney J, Johannsson G, Leung KC, Ho KKY. Comparison of the metabolic effects of raloxifene and oral estrogen in postmenopausal and growth hormone-deficient women. J Clin Endocrinol Metab 2005 90 : 3897 3903.
77. Tarnopolsky MA. Sex differences in exercise metabolism and the role of 17-beta estradiol. Med Sci Sports Exerc 2008 40 : 648 654.
78. Venables MC, Achten J, Jeukendrup AE. Determinants of fat oxidation during exercise in healthy men and women: a cross-sectional study. J Appl Physiol 2005 98 : 160 167.
79. Carter SL, Rennie CD, Tarnopolsky MA. Substrate utilization during endurance exercise in men and women after endurance training. Am J Physiol 2001 280 : E898 E907.
80. Ruby BC, Coogan AR, Zderic TW. Gender differences in glucose kinetics and substrate oxidation during exercise near the lactate threshold. J Appl Physiol 2002 92 : 1125 1132.
81. D'Eon TM, Sharoff C, Chipkin SR, Grow D, Ruby BC, Braun B. Regulation of exercise carbohydrate metabolism by estrogen and progesterone in women. Am J Physiol 2002 283 : E1046 E1055.
82. Henderson GC, Fattor JA, Horning MA, Faghihnia N, Johnson ML, Mau TL, Luke-Zeitoun M, Brooks GA. Lipolysis and fatty acid metabolism in men and women during the postexercise recovery period. J Physiol 2007 584 : 963 981.
83. Tarnopolsky MA, Rennie CD, Robertshaw HA, Fedak-Tarnopolsky SN, Devries MC, Hamadeh MJ. Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity. Am J Physiol Regul Integr Comp Physiol 2007 292 : R1271 R8.
84. Donnelly JE, Smith BK. Is exercise for weight loss with ad libitum diet? Energy balance, compensation, and gender differences. Exerc Sport Sci Rev 2005 33 : 169 174.
85. Andersen JW, Grant L, Gotthelf L, Stifler LT. Weight loss and long-term follow-up of severely obese individuals treated with an intense behavioral program. Int J Obes 2006 31 : 488 493.
86. Binnert C, Koistinen HA, Martin G, Andreelli F, Ebeling P, Koivisto VA, Laville M, Auwerx J, Vidal H. Fatty acid transport protein-1 mRNA expression in skeltal muscle and in adipose tissue in humans. Am J Physiol 2000 279 : E1072 E1079.
87. 14C] Oleate by perfused livers and hepatocytes from female rats. Biochem J 1979 180 : 265 271.
88. Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role on metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008 7 : 489 503.
89. Bass NM, Manning JA, Ockner RK, Gordon JI, Seetharam S, Alpers DH. Regulation of the biosynthesis of two distinct fatty acid-binding proteins in rat liver and intestine. Influences of sex difference and of clofibrate. J Biol Chem 1985 260 : 1432 1436.
90. Dube N, Delvin E, Yotov W, Garofalo C, Bendayan M, Veerkamp JH, Levy E. Modulation of intestinal and liver fatty acid-binding proteins in Caco-2 cells by lipids, hormones and cytokines. J Cell Biochem 2001 81 : 613 620.
91. Veerkamp JH, Maatman RG. Cytoplasmic fatty acid-binding proteins: their structure and genes. Prog Lipid Res 1995 34 : 17 52.
92. Martin GG, Atshaves BP, McIntosh AL, Mackie JT, Kier AB, Schroeder F. Liver fatty acid binding protein gene ablation potentiates hepatic cholesterol accumulation in cholesterol-fed female mice. Am J Physiol 2006 290 : G36 G48.
93. Atshaves BP, McIntosh AM, Lyuksyutova OI, Zipfel W, Webb WW, Schroeder F. Liver fatty acid-binding protein gene ablation inhibits branched-chain fatty acid metabolism in cultured primary hepatocytes. J Biol Chem 2004 279 : 30954 30965.
94. Newberry EP, Kennedy SM, Yan X, Sternard BT, Luo J, Davidson N. Diet-induced obesity and hepatic steatosis in L-Fabp / mice is abrogated with SF, but not PUFA, feeding and attenuated after cholesterol supplementation. Am J Physiol 2008 295 : G307 G14.
95. Leung KC, Doyle N, Ballesteros M, Sjogren K, Watts CK, Low TH, Leong GM, Ross RJ, Ho KKY. Estrogen inhibits GH signaling by suppressing GH-induced phosphorylation, an effect mediated by SOCS-2. Proc Natl Acad Sci 2003 100 : 1016 1021.
96. Moller N, Jorgensen JOL, Alberti KGMM, Flyvbjerg A, Schmitz O. Short-term effects of growth hormone on fuel oxidation and regional substrate metabolism in normal man. J Clin Endocrinol Metab 1990 70 : 1179 1186.
97. O'Sullivan AJ, Kelly JJ, Hoffman DM, Freund J, Ho KKY. Body composition and energy expenditure in acromegaly. J Clin Endocrinol Metab 1994 78 : 381 386.
98. O'Sullivan AJ, Ho KKY. Route-dependent endocrine and metabolic effects of estrogen replacement therapy. J Pediatr Endocrinol 2000 13 (Suppl. 6 1457 1466.
99. Ho KY, Valiontis E, Waters MJ, Rajkovic IA. Regulation of growth hormone binding protein in man: comparison of gel chromatography and immunoprecipitation methods. J Clin Endocrinol Metab 1993 76 : 302 308.
100. Wolthers T, Hoffman DH, Nugent AG, Duncan M, Sonkson P, Ho KKY. Oral oestrogen impairs the metabolic effects of growth hormone (GH) in GH deficient women. Am J Physiol 2001 281 : E1191 E1196.
101. Chan JL, Mantzoros CS. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhea and anorexia nervosa. Lancet 2005 366 : 74 85.
102. Schneider JE. Energy balance and reproduction. Physiol Behav 2004 81 : 289 317.
103. Gao Q, Horvarth TL. Cross-talk between estrogen and leptin signalling in the hypothalamus. Am J Physiol 2008 294 : E817 E826.
104. Weinstein I, Cook GA, Heimberg M. Regulation by oestrogen of carnitine palmitoyltransferase in hepatic mitochondria. Biochem J 1986 237 : 593 596.
105. Campbell SE, Febbraio MA. Effect of ovarian hormones on mitochondrial enzyme activity in the fat oxidation pathway of skeletal muscle. Am J Physiol 2001 281 : E803 E808.
106. Berthon PM, Howlett RA, Heigenhauser GJ, Spriet LL. Human skeletal muscle carnitine palmitoyltransferase I activity determined in isolated mitochondria. J Appl Physiol 1998 85 : 148 153.
107. O'Sullivan AJ, Ho KKY. A comparison of the effects of oral and transdermal estrogen replacement therapy on insulin sensitivity in postmenopausal women. J Clin Endocrinol Metab 1995 80 : 1783 1788.
108. Fineberg SE. Glycaemic control and hormone replacement therapy: implications of the Postmenopausal Estrogen/Progestogen Intervention (PEPI) study. Drugs Aging 2000 17 : 453 461.
109. Godsland IF, Ganger K, Walton C, Cust MP, Whitehead MI, Wynn V, Stevenson JC. Insulin resistance, secretion, and elimination in postmenopausal women receiving oral and transdermal hormone replacement therapy. Metabolism 1993 42 : 846 853.