Effect of oral estrogen on substrate utilization in postmenopausal women
2007; Elsevier BV; Volume: 90; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2007.07.1317
ISSN1556-5653
AutoresRebecca Lwin, Betty E. Darnell, Robert A. Oster, Jeannine C. Lawrence, Jill A. Foster, Ricardo Azziz, Barbara A. Gower,
Tópico(s)Hormonal and reproductive studies
ResumoWe tested the hypothesis that a 2-month intervention with unopposed oral conjugated equine estrogens (0.625 mg/d) would decrease lipid oxidation, as assessed by 24-hour, whole-room, indirect calorimetry in 14 postmenopausal women. Estrogen (E) treatment was associated with declines in both 24-hour and postprandial lipid oxidation and an increase in fat mass (mean [±SD] 2-month difference 1.1 ± 1.0 kg; mean 6-month difference 1.8 ± 2.2 kg), suggesting that, on an acute basis, oral E may increase adiposity by limiting lipid oxidation. We tested the hypothesis that a 2-month intervention with unopposed oral conjugated equine estrogens (0.625 mg/d) would decrease lipid oxidation, as assessed by 24-hour, whole-room, indirect calorimetry in 14 postmenopausal women. Estrogen (E) treatment was associated with declines in both 24-hour and postprandial lipid oxidation and an increase in fat mass (mean [±SD] 2-month difference 1.1 ± 1.0 kg; mean 6-month difference 1.8 ± 2.2 kg), suggesting that, on an acute basis, oral E may increase adiposity by limiting lipid oxidation. The perception that postmenopausal hormone replacement therapy (HRT) causes weight gain is a major cause of noncompliance (1Nachtigall L.E. Enhancing patient compliance with hormone replacement therapy at menopause.Obstet Gynecol. 1990; 75: 77S-80SPubMed Google Scholar). This perception is paradoxical, in that numerous studies have suggested that exogenous E limits weight and/or fat gain (2Tchernof A. Calles-Escandon J. Sites C.K. Poehlman E.T. Menopause, central body fatness, and insulin resistance: effects of hormone replacement therapy.Coron Artery Dis. 1998; 9: 503-511Crossref PubMed Scopus (144) Google Scholar, 3Mayes J.S. Watson G.H. Direct effects of sex steroid hormones on adipose tissues and obesity.Obes Rev. 2004; 5: 197-216Crossref PubMed Scopus (367) Google Scholar, 4Wade G.N. Schneider J.E. Metabolic fuels and reproduction in female mammals.Neurosci Biobehav Rev. 1992; 16: 235-272Crossref PubMed Scopus (565) Google Scholar). Perceptions of weight gain among HRT users may be based on acute increases in body weight/fat, such as have been reported after 6–12 months of oral E treatment (5Spellacy W.N. Buhi W.C. Birk S.A. The effect of estrogens on carbohydrate metabolism: glucose, insulin, and growth hormone studies on one hundred and seventy-one women ingesting Premarin, mestranol, and ethinyl estradiol for six months.Am J Obstet Gynecol. 1972; 114: 378-392Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar).On an acute basis, oral E may increase fat deposition by decreasing lipid oxidation. Exposure of the liver to high concentrations of E decreases enzymes involved in lipid oxidation (9Weinstein I. Cook G.A. Heimberg M. Regulation by oestrogen of carnitine palmitoyltransferase in hepatic mitochondria.Biochem J. 1986; 237: 593-596Crossref PubMed Scopus (31) Google Scholar, 10Gower B.A. Nagy T.R. Blaylock M.L. Wang C. Nyman L. Estradiol may limit lipid oxidation via CPT 1 expression and hormonal mechanisms.Obes Res. 2002; 10: 167-172Crossref PubMed Scopus (23) Google Scholar) and increases enzymes involved in lipogenesis (11Mandour T. Kissebah A.H. Wynn V. Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity.Eur J Clin Invest. 1977; 7: 181-187Crossref PubMed Scopus (89) Google Scholar). Data from rodent models have shown that pharmacological doses of E depress both messenger RNA (10Gower B.A. Nagy T.R. Blaylock M.L. Wang C. Nyman L. Estradiol may limit lipid oxidation via CPT 1 expression and hormonal mechanisms.Obes Res. 2002; 10: 167-172Crossref PubMed Scopus (23) Google Scholar) and protein (9Weinstein I. Cook G.A. Heimberg M. Regulation by oestrogen of carnitine palmitoyltransferase in hepatic mitochondria.Biochem J. 1986; 237: 593-596Crossref PubMed Scopus (31) Google Scholar) of carnitine palmitoyl transferase-1, the enzyme that transfers fatty acids into the mitochondria, the rate-limiting step in lipid oxidation, and elevate circulating triglycerides (11Mandour T. Kissebah A.H. Wynn V. Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity.Eur J Clin Invest. 1977; 7: 181-187Crossref PubMed Scopus (89) Google Scholar).Similarly in women, oral E is associated with a decrease in lipid oxidation (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar). In contrast, transdermal E, which is not subject to the first-pass effect, does not affect lipid oxidation (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). The liver is responsible for 21%–27% of whole-body resting metabolism (12McArdle W.D. Katch F.I. Katch V.L. Energy expenditure at rest. Exercise physiology: energy, nutrition, and human performance. Lea and Febiger, Malvern, PA1991Google Scholar, 13Schutz Y. Jequier E. Resting energy expenditure, thermic effect of food, and total energy expenditure.in: Bray G.A. Bouchard C. Handbook of obesity. Marcel Dekker, New York1998: 443-455Google Scholar, 14Konarzewski M. Diamond J. Evolution of basal metabolic rate and organ masses in laboratory mice.Evolution. 1995; 49: 1239-1248Crossref Google Scholar) and oxidizes a higher proportion of lipid than does skeletal muscle. Estrogen-mediated changes in hepatic substrate metabolism could have an impact on whole-body energy partitioning (8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar).Studies are needed that carefully examine the metabolic effects of initiation of HRT. We tested the hypothesis that initiation of oral E treatment would, acutely, suppress lipid oxidation. Because E may modify food intake (15Dagnault A. Ouerghi D. Richard D. Treatment with alpha-helical-CRF(9-41) prevents the anorectic effect of 17-beta-estradiol.Brain Res Bull. 1993; 32: 689-692Crossref PubMed Scopus (58) Google Scholar), and because both diet quantity and quality affect substrate utilization (13Schutz Y. Jequier E. Resting energy expenditure, thermic effect of food, and total energy expenditure.in: Bray G.A. Bouchard C. Handbook of obesity. Marcel Dekker, New York1998: 443-455Google Scholar), the design of the study involved strict weight maintenance and dietary control before metabolic testing.Participants were 14 postmenopausal women, defined as cessation of menstruation of at least 12 months (mean was 1.5 years), or hysterectomy, and FSH level >30 IU/mL (FSH ranged 44–138 IU/mL), who had not used HRT within 2 years and were weight stable (±2.3 kg) within the last year. The protocol was approved by the institutional review board of the University of Alabama at Birmingham (UAB), and all participants gave their informed consent before participation. This pilot study was designed such that each woman would serve as her own control. Because of limited resources and the demanding nature of the testing protocol, it was not feasible to include a placebo group or to retest (cross-over) the subjects under placebo-treated conditions.Comprehensive metabolic testing was conducted on an in-patient basis at baseline and after 2 months of E treatment; body composition also was reassessed at 6 months. Before metabolic testing, participants underwent 3 days of supervised weight maintenance, during which all food was provided by the General Clinical Research Center at UAB. A computed tomography scan was performed for determination of intra-abdominal fat and subcutaneous abdominal adipose tissue (16Gower B.A. Munoz J. Desmond R. Hilario-Hailey T. Jiao X. Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use.Obesity. 2006; 14: 1046-1055Crossref PubMed Scopus (34) Google Scholar). Body composition was determined by dual-energy x-ray absorptiometry (DXA [16]). Twenty-four-hour substrate utilization was determined by whole-room indirect calorimetry (17Treuth M.S. Hunter G.R. Weinsier R.L. Kell S.H. Energy expenditure and substrate utilization in older women after strength training: 24-h calorimeter results.J Appl Physiol. 1995; 78: 2140-2146PubMed Google Scholar). Respiratory quotient (RQ) was used as an index of lipid oxidation (higher RQ = lesser lipid oxidation). Respiratory quotient was averaged over the entire period during which the subject was in the calorimeter and expressed normalized to 24 hours. Resting RQ was determined during a 30-minute period in the morning, immediately after the subject was awakened, while she was lying in bed. In addition, RQ was determined for each postprandial period, which was defined as the time participants began eating a meal until 3 hours after completing the meal. Urine was collected throughout the period during which each subject resided in the calorimeter and was analyzed for nitrogen content. The insulin sensitivity index (Si) from minimal modeling was calculated using data obtained during an insulin-modified IV glucose tolerance test (18Pacini G. Tonolo G. Sambataro M. Maioli M. Ciccarese M. Brocco E. et al.Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT.Am J Physiol. 1998; 274: E592-E599PubMed Google Scholar). Information on free-living diet was collected by 7-day food record before admission (19Schakel S.F. Sievert Y.A. Buzzard I.M. Sources of data for developing and maintaining a nutrient database.J Am Diet Assoc. 1988; 88: 1268-1271PubMed Google Scholar). After completion of the baseline metabolic evaluation, participants initiated treatment with conjugated equine E (CEE; 0.625 mg/day).Mixed-model, repeated-measures analysis of variance was used to analyze 24-hour RQ, postprandial RQ, and body composition. In the case of postprandial RQ, the model simultaneously accounted for the three meals (breakfast, lunch, and dinner). Paired t-tests were used for analyses of Si, urinary nitrogen, and dietary intake. Pearson correlation analysis was used to examine associations between changes in Si, total fat mass, intra-abdominal fat, body weight, dietary energy, and dietary fat. All tests were two sided and were performed at a 5% significance level using commercial software (SAS 9.1; SAS Institute, Cary, NC).Of the 15 participants who completed the baseline evaluation and began the E intervention, 14 completed the 2-month evaluation. Of these 14 participants, 13 completed the 6-month evaluation. At baseline, participants were aged 51.3 ± 3.9 years (mean ± SD; range 46–60 years) and weighed 74.1 ± 13.5 kg (range 56.8–99.9 kg). For Si the participant number was 13 because Si could not be estimated by the MINMOD software (Richard N. Bergman, University of Southern California, Los Angeles, CA) in 1 subject at the 2-month evaluation.Metabolic data at baseline and 2 months and body composition at 6 months are shown in Table 1. Twenty-four-hour RQ was significantly higher at 2 months compared with baseline. Similarly, when data from all meals were examined simultaneously, a significant difference was found in postprandial RQ before and after the E intervention. Post hoc analyses indicated that, for the lunch meal, there was a significant difference between the mean RQ at baseline and the mean RQ after the E intervention. The Si was significantly lower after 2 months of E use. The change in Si was correlated with neither the change in total fat mass (r = −0.04, P=.905) nor the change in intra-abdominal fat (r = −0.09, P=.778). Participants gained significant fat mass between baseline and 2 months and between baseline and 6 months. The gain in total fat mass was reflected in gains in trunk fat mass (9.4%) and leg fat mass (11.8%) that were significant at 6 months but not 2 months. Dietary intake did not change significantly from baseline to 2 months. Changes in intake of neither total energy nor fat (grams) were correlated with changes in body weight or total body fat mass.Table 1Metabolic outcomes at baseline and after estrogen treatment.Baseline2 mo6 mo24-h energy expenditure (kcal/day)1,720 ± 2061,664 ± 204—24-h RQ0.8648 ± 0.01580.8756 ± 0.0162aP<.05 vs. baseline.—Resting RQ0.8522 ± 0.06710.8488 ± 0.0304—Breakfast RQ0.8861 ± 0.03580.8954 ± 0.0398—Lunch RQ0.8729 ± 0.02660.8920 ± 0.0351aP<.05 vs. baseline.—Dinner RQ0.8731 ± 0.03630.8885 ± 0.0288—Combined postprandial RQ0.8774 ± 0.03300.8920 ± 0.0341aP<.05 vs. baseline.—24-h urinary N2 (mg/d)8,075 ± 2,17710,002 ± 3,680bP=.06 vs. baseline.—Fasting insulin (pmol/L)66 ± 3066 ± 24—Si (×10-4min-1/(uIU/mL))4.13 ± 2.432.99 ± 2.07aP<.05 vs. baseline.—Lean body mass (kg)38.5 ± 6.238.8 ± 4.739.4 ± 5.1Fat mass (kg)31.6 ± 9.932.7 ± 10.4aP<.05 vs. baseline.33.5 ± 10.0aP<.05 vs. baseline.Trunk fat (kg)14.61 ± 5.6715.45 ± 5.5115.99 ± 5.74aP<.05 vs. baseline.Leg fat (kg)11.56 ± 4.0512.27 ± 3.7712.93 ± 3.48aP<.05 vs. baseline.IAAT (cm2)139 ± 55130 ± 56—SAAT (cm2)371 ± 137324 ± 149—Total body mass (kg)74.1 ± 13.574.6 ± 13.076.6 ± 14.0aP<.05 vs. baseline.cP<.05 vs. 2 mo.Note: RQ = respiratory quotient; Si = insulin sensitivity index; IAAT = intra-abdominal fat; SAAT = subcutaneous abdominal adipose tissue.Values are mean ± SD.a P<.05 vs. baseline.b P=.06 vs. baseline.c P<.05 vs. 2 mo. Open table in a new tab These results indicate that short-term treatment with oral E was associated with decreases in 24-hour and postprandial lipid oxidation as assessed with whole-room indirect calorimetry. These findings complement and extend those of earlier studies showing that postmenopausal oral E (alone or in combination with progestin) decreased lipid oxidation assessed using a Deltatrac metabolic monitor (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). The present study and an earlier study (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar) detected an E-related decrease in lipid oxidation in the postprandial but not fasted state. It is possible that oral E affects aspects of insulin secretion, clearance, or action after meal ingestion and that these effects are reflected in substrate utilization. The only other study to examine the RQ response to postmenopausal oral E therapy examined only the fasting condition and observed a decline in fat oxidation with E use (7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Further study is warranted to characterize the effects of oral E on fasting and postprandial substrate metabolism and to identify the mechanism through which it affects substrate metabolism.In this study, 6 months of oral E use was also associated with an increase in fat mass, as reported in some (5Spellacy W.N. Buhi W.C. Birk S.A. The effect of estrogens on carbohydrate metabolism: glucose, insulin, and growth hormone studies on one hundred and seventy-one women ingesting Premarin, mestranol, and ethinyl estradiol for six months.Am J Obstet Gynecol. 1972; 114: 378-392Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar) but not all studies. Differences among studies may indicate that heterogeneity exists in the response of women to HRT. It has been reported that only women in the overweight to moderately obese body mass index range (27–32 kg/m2) experience weight gain when they initiate oral E (20Mogul HR, Wynn PS, Frey M, Buddala S, Carosella C, Weinstein BI, Wilker S, Mogul DB. Weight gain in menopause: the role of estrogen replacement and other factors. Endocrine Society Annual Meeting, Bethesda, MD. 1998;P2-539:362.Google Scholar). Alternatively, the acute metabolic, lipogenic effects of oral E may be offset over time by beneficial effects on behavior and energy expenditure, such as have been observed in animal models (4Wade G.N. Schneider J.E. Metabolic fuels and reproduction in female mammals.Neurosci Biobehav Rev. 1992; 16: 235-272Crossref PubMed Scopus (565) Google Scholar).Over the 6-month treatment period, the women in the present study gained approximately proportionate amounts of fat mass in the trunk (9.4% increase) and leg (11.8% increase) regions, as determined by DXA. This pattern of fat gain matches that observed among untreated postmenopausal women who, over 3 years, deposited approximately equivalent amounts of fat in the leg (20% increase) and trunk (26% increase) regions. In contrast, women treated with estradiol valerate and cyproterone acetate deposited fat solely in the leg region (43% increase) (21Gambacciani M. Ciaponi M. Cappagli B. De Simone L. Orlandi R. Genazzani A.R. Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.Maturitas. 2001; 39: 125-132Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Differences in the pattern of fat deposition between the two studies may relate to the nature of the hormone treatment; the present study involved administration of unopposed oral CEE, whereas the study by Gambaccianai et al. (21Gambacciani M. Ciaponi M. Cappagli B. De Simone L. Orlandi R. Genazzani A.R. Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.Maturitas. 2001; 39: 125-132Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) involved administration of oral E2 and an oral progestin. It is possible that either CEE differs from E2 in its effects on fat distribution or that a combination of E and progestin is required for preferential deposition of leg fat. Because storage of triglyceride in the leg region may have “protective” effects regarding risk for chronic metabolic disease among women in this age group (22Van Pelt R.E. Evans E.M. Schechtman K.B. Ehsani A.A. Kohrt W.M. Contributions of total and regional fat mass to risk for cardiovascular disease in older women.Am J Physiol. 2002; 282: E1023-E1028PubMed Google Scholar), it is important to characterize the endocrine environment that promotes deposition of fat in the femoral region.In conclusion, 2 months of treatment with unopposed oral E was associated with declines in both 24-hour and postprandial, but not fasting, lipid oxidation. On an acute basis, this decrease in lipid oxidation may lead to a gain in fat mass, which is a perception voiced by many women initiating postmenopausal hormone therapy. However, acute metabolic effects of E treatment may be balanced over time by beneficial effects on food intake and physical activity. An improved understanding of both the acute and chronic effects of HRT on metabolism, body composition, and fat distribution may be helpful for women initiating HRT. The perception that postmenopausal hormone replacement therapy (HRT) causes weight gain is a major cause of noncompliance (1Nachtigall L.E. Enhancing patient compliance with hormone replacement therapy at menopause.Obstet Gynecol. 1990; 75: 77S-80SPubMed Google Scholar). This perception is paradoxical, in that numerous studies have suggested that exogenous E limits weight and/or fat gain (2Tchernof A. Calles-Escandon J. Sites C.K. Poehlman E.T. Menopause, central body fatness, and insulin resistance: effects of hormone replacement therapy.Coron Artery Dis. 1998; 9: 503-511Crossref PubMed Scopus (144) Google Scholar, 3Mayes J.S. Watson G.H. Direct effects of sex steroid hormones on adipose tissues and obesity.Obes Rev. 2004; 5: 197-216Crossref PubMed Scopus (367) Google Scholar, 4Wade G.N. Schneider J.E. Metabolic fuels and reproduction in female mammals.Neurosci Biobehav Rev. 1992; 16: 235-272Crossref PubMed Scopus (565) Google Scholar). Perceptions of weight gain among HRT users may be based on acute increases in body weight/fat, such as have been reported after 6–12 months of oral E treatment (5Spellacy W.N. Buhi W.C. Birk S.A. The effect of estrogens on carbohydrate metabolism: glucose, insulin, and growth hormone studies on one hundred and seventy-one women ingesting Premarin, mestranol, and ethinyl estradiol for six months.Am J Obstet Gynecol. 1972; 114: 378-392Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar). On an acute basis, oral E may increase fat deposition by decreasing lipid oxidation. Exposure of the liver to high concentrations of E decreases enzymes involved in lipid oxidation (9Weinstein I. Cook G.A. Heimberg M. Regulation by oestrogen of carnitine palmitoyltransferase in hepatic mitochondria.Biochem J. 1986; 237: 593-596Crossref PubMed Scopus (31) Google Scholar, 10Gower B.A. Nagy T.R. Blaylock M.L. Wang C. Nyman L. Estradiol may limit lipid oxidation via CPT 1 expression and hormonal mechanisms.Obes Res. 2002; 10: 167-172Crossref PubMed Scopus (23) Google Scholar) and increases enzymes involved in lipogenesis (11Mandour T. Kissebah A.H. Wynn V. Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity.Eur J Clin Invest. 1977; 7: 181-187Crossref PubMed Scopus (89) Google Scholar). Data from rodent models have shown that pharmacological doses of E depress both messenger RNA (10Gower B.A. Nagy T.R. Blaylock M.L. Wang C. Nyman L. Estradiol may limit lipid oxidation via CPT 1 expression and hormonal mechanisms.Obes Res. 2002; 10: 167-172Crossref PubMed Scopus (23) Google Scholar) and protein (9Weinstein I. Cook G.A. Heimberg M. Regulation by oestrogen of carnitine palmitoyltransferase in hepatic mitochondria.Biochem J. 1986; 237: 593-596Crossref PubMed Scopus (31) Google Scholar) of carnitine palmitoyl transferase-1, the enzyme that transfers fatty acids into the mitochondria, the rate-limiting step in lipid oxidation, and elevate circulating triglycerides (11Mandour T. Kissebah A.H. Wynn V. Mechanism of oestrogen and progesterone effects on lipid and carbohydrate metabolism: alteration in the insulin: glucagon molar ratio and hepatic enzyme activity.Eur J Clin Invest. 1977; 7: 181-187Crossref PubMed Scopus (89) Google Scholar). Similarly in women, oral E is associated with a decrease in lipid oxidation (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar). In contrast, transdermal E, which is not subject to the first-pass effect, does not affect lipid oxidation (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). The liver is responsible for 21%–27% of whole-body resting metabolism (12McArdle W.D. Katch F.I. Katch V.L. Energy expenditure at rest. Exercise physiology: energy, nutrition, and human performance. Lea and Febiger, Malvern, PA1991Google Scholar, 13Schutz Y. Jequier E. Resting energy expenditure, thermic effect of food, and total energy expenditure.in: Bray G.A. Bouchard C. Handbook of obesity. Marcel Dekker, New York1998: 443-455Google Scholar, 14Konarzewski M. Diamond J. Evolution of basal metabolic rate and organ masses in laboratory mice.Evolution. 1995; 49: 1239-1248Crossref Google Scholar) and oxidizes a higher proportion of lipid than does skeletal muscle. Estrogen-mediated changes in hepatic substrate metabolism could have an impact on whole-body energy partitioning (8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar). Studies are needed that carefully examine the metabolic effects of initiation of HRT. We tested the hypothesis that initiation of oral E treatment would, acutely, suppress lipid oxidation. Because E may modify food intake (15Dagnault A. Ouerghi D. Richard D. Treatment with alpha-helical-CRF(9-41) prevents the anorectic effect of 17-beta-estradiol.Brain Res Bull. 1993; 32: 689-692Crossref PubMed Scopus (58) Google Scholar), and because both diet quantity and quality affect substrate utilization (13Schutz Y. Jequier E. Resting energy expenditure, thermic effect of food, and total energy expenditure.in: Bray G.A. Bouchard C. Handbook of obesity. Marcel Dekker, New York1998: 443-455Google Scholar), the design of the study involved strict weight maintenance and dietary control before metabolic testing. Participants were 14 postmenopausal women, defined as cessation of menstruation of at least 12 months (mean was 1.5 years), or hysterectomy, and FSH level >30 IU/mL (FSH ranged 44–138 IU/mL), who had not used HRT within 2 years and were weight stable (±2.3 kg) within the last year. The protocol was approved by the institutional review board of the University of Alabama at Birmingham (UAB), and all participants gave their informed consent before participation. This pilot study was designed such that each woman would serve as her own control. Because of limited resources and the demanding nature of the testing protocol, it was not feasible to include a placebo group or to retest (cross-over) the subjects under placebo-treated conditions. Comprehensive metabolic testing was conducted on an in-patient basis at baseline and after 2 months of E treatment; body composition also was reassessed at 6 months. Before metabolic testing, participants underwent 3 days of supervised weight maintenance, during which all food was provided by the General Clinical Research Center at UAB. A computed tomography scan was performed for determination of intra-abdominal fat and subcutaneous abdominal adipose tissue (16Gower B.A. Munoz J. Desmond R. Hilario-Hailey T. Jiao X. Changes in intra-abdominal fat in early postmenopausal women: effects of hormone use.Obesity. 2006; 14: 1046-1055Crossref PubMed Scopus (34) Google Scholar). Body composition was determined by dual-energy x-ray absorptiometry (DXA [16]). Twenty-four-hour substrate utilization was determined by whole-room indirect calorimetry (17Treuth M.S. Hunter G.R. Weinsier R.L. Kell S.H. Energy expenditure and substrate utilization in older women after strength training: 24-h calorimeter results.J Appl Physiol. 1995; 78: 2140-2146PubMed Google Scholar). Respiratory quotient (RQ) was used as an index of lipid oxidation (higher RQ = lesser lipid oxidation). Respiratory quotient was averaged over the entire period during which the subject was in the calorimeter and expressed normalized to 24 hours. Resting RQ was determined during a 30-minute period in the morning, immediately after the subject was awakened, while she was lying in bed. In addition, RQ was determined for each postprandial period, which was defined as the time participants began eating a meal until 3 hours after completing the meal. Urine was collected throughout the period during which each subject resided in the calorimeter and was analyzed for nitrogen content. The insulin sensitivity index (Si) from minimal modeling was calculated using data obtained during an insulin-modified IV glucose tolerance test (18Pacini G. Tonolo G. Sambataro M. Maioli M. Ciccarese M. Brocco E. et al.Insulin sensitivity and glucose effectiveness: minimal model analysis of regular and insulin-modified FSIGT.Am J Physiol. 1998; 274: E592-E599PubMed Google Scholar). Information on free-living diet was collected by 7-day food record before admission (19Schakel S.F. Sievert Y.A. Buzzard I.M. Sources of data for developing and maintaining a nutrient database.J Am Diet Assoc. 1988; 88: 1268-1271PubMed Google Scholar). After completion of the baseline metabolic evaluation, participants initiated treatment with conjugated equine E (CEE; 0.625 mg/day). Mixed-model, repeated-measures analysis of variance was used to analyze 24-hour RQ, postprandial RQ, and body composition. In the case of postprandial RQ, the model simultaneously accounted for the three meals (breakfast, lunch, and dinner). Paired t-tests were used for analyses of Si, urinary nitrogen, and dietary intake. Pearson correlation analysis was used to examine associations between changes in Si, total fat mass, intra-abdominal fat, body weight, dietary energy, and dietary fat. All tests were two sided and were performed at a 5% significance level using commercial software (SAS 9.1; SAS Institute, Cary, NC). Of the 15 participants who completed the baseline evaluation and began the E intervention, 14 completed the 2-month evaluation. Of these 14 participants, 13 completed the 6-month evaluation. At baseline, participants were aged 51.3 ± 3.9 years (mean ± SD; range 46–60 years) and weighed 74.1 ± 13.5 kg (range 56.8–99.9 kg). For Si the participant number was 13 because Si could not be estimated by the MINMOD software (Richard N. Bergman, University of Southern California, Los Angeles, CA) in 1 subject at the 2-month evaluation. Metabolic data at baseline and 2 months and body composition at 6 months are shown in Table 1. Twenty-four-hour RQ was significantly higher at 2 months compared with baseline. Similarly, when data from all meals were examined simultaneously, a significant difference was found in postprandial RQ before and after the E intervention. Post hoc analyses indicated that, for the lunch meal, there was a significant difference between the mean RQ at baseline and the mean RQ after the E intervention. The Si was significantly lower after 2 months of E use. The change in Si was correlated with neither the change in total fat mass (r = −0.04, P=.905) nor the change in intra-abdominal fat (r = −0.09, P=.778). Participants gained significant fat mass between baseline and 2 months and between baseline and 6 months. The gain in total fat mass was reflected in gains in trunk fat mass (9.4%) and leg fat mass (11.8%) that were significant at 6 months but not 2 months. Dietary intake did not change significantly from baseline to 2 months. Changes in intake of neither total energy nor fat (grams) were correlated with changes in body weight or total body fat mass. Note: RQ = respiratory quotient; Si = insulin sensitivity index; IAAT = intra-abdominal fat; SAAT = subcutaneous abdominal adipose tissue. Values are mean ± SD. These results indicate that short-term treatment with oral E was associated with decreases in 24-hour and postprandial lipid oxidation as assessed with whole-room indirect calorimetry. These findings complement and extend those of earlier studies showing that postmenopausal oral E (alone or in combination with progestin) decreased lipid oxidation assessed using a Deltatrac metabolic monitor (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). The present study and an earlier study (6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar) detected an E-related decrease in lipid oxidation in the postprandial but not fasted state. It is possible that oral E affects aspects of insulin secretion, clearance, or action after meal ingestion and that these effects are reflected in substrate utilization. The only other study to examine the RQ response to postmenopausal oral E therapy examined only the fasting condition and observed a decline in fat oxidation with E use (7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Further study is warranted to characterize the effects of oral E on fasting and postprandial substrate metabolism and to identify the mechanism through which it affects substrate metabolism. In this study, 6 months of oral E use was also associated with an increase in fat mass, as reported in some (5Spellacy W.N. Buhi W.C. Birk S.A. The effect of estrogens on carbohydrate metabolism: glucose, insulin, and growth hormone studies on one hundred and seventy-one women ingesting Premarin, mestranol, and ethinyl estradiol for six months.Am J Obstet Gynecol. 1972; 114: 378-392Abstract Full Text PDF PubMed Scopus (124) Google Scholar, 6O'Sullivan A.J. Crampton L.J. Freund J. Ho K.Y. The route of estrogen replacement therapy confers divergent effects on substrate oxidation and body composition in postmenopausal women.J Clin Invest. 1998; 102: 1035-1040Crossref PubMed Scopus (187) Google Scholar, 7dos Reis C.M.R.F. de Melo N.R. Meirelles E.S. Vezozzo D.P. Halpern A. Body composition, visceral fat distribution and fat oxidation in postmenopausal women using oral or transdermal oestrogen.Maturitas. 2003; 46: 59-68Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 8O'Sullivan A.J. Hoffman D.H. Ho K.Y. Estrogen, lipid oxidation, and body fat.N Engl J Med. 1995; 333: 669-670Crossref PubMed Scopus (41) Google Scholar) but not all studies. Differences among studies may indicate that heterogeneity exists in the response of women to HRT. It has been reported that only women in the overweight to moderately obese body mass index range (27–32 kg/m2) experience weight gain when they initiate oral E (20Mogul HR, Wynn PS, Frey M, Buddala S, Carosella C, Weinstein BI, Wilker S, Mogul DB. Weight gain in menopause: the role of estrogen replacement and other factors. Endocrine Society Annual Meeting, Bethesda, MD. 1998;P2-539:362.Google Scholar). Alternatively, the acute metabolic, lipogenic effects of oral E may be offset over time by beneficial effects on behavior and energy expenditure, such as have been observed in animal models (4Wade G.N. Schneider J.E. Metabolic fuels and reproduction in female mammals.Neurosci Biobehav Rev. 1992; 16: 235-272Crossref PubMed Scopus (565) Google Scholar). Over the 6-month treatment period, the women in the present study gained approximately proportionate amounts of fat mass in the trunk (9.4% increase) and leg (11.8% increase) regions, as determined by DXA. This pattern of fat gain matches that observed among untreated postmenopausal women who, over 3 years, deposited approximately equivalent amounts of fat in the leg (20% increase) and trunk (26% increase) regions. In contrast, women treated with estradiol valerate and cyproterone acetate deposited fat solely in the leg region (43% increase) (21Gambacciani M. Ciaponi M. Cappagli B. De Simone L. Orlandi R. Genazzani A.R. Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.Maturitas. 2001; 39: 125-132Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar). Differences in the pattern of fat deposition between the two studies may relate to the nature of the hormone treatment; the present study involved administration of unopposed oral CEE, whereas the study by Gambaccianai et al. (21Gambacciani M. Ciaponi M. Cappagli B. De Simone L. Orlandi R. Genazzani A.R. Prospective evaluation of body weight and body fat distribution in early postmenopausal women with and without hormonal replacement therapy.Maturitas. 2001; 39: 125-132Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar) involved administration of oral E2 and an oral progestin. It is possible that either CEE differs from E2 in its effects on fat distribution or that a combination of E and progestin is required for preferential deposition of leg fat. Because storage of triglyceride in the leg region may have “protective” effects regarding risk for chronic metabolic disease among women in this age group (22Van Pelt R.E. Evans E.M. Schechtman K.B. Ehsani A.A. Kohrt W.M. Contributions of total and regional fat mass to risk for cardiovascular disease in older women.Am J Physiol. 2002; 282: E1023-E1028PubMed Google Scholar), it is important to characterize the endocrine environment that promotes deposition of fat in the femoral region. In conclusion, 2 months of treatment with unopposed oral E was associated with declines in both 24-hour and postprandial, but not fasting, lipid oxidation. On an acute basis, this decrease in lipid oxidation may lead to a gain in fat mass, which is a perception voiced by many women initiating postmenopausal hormone therapy. However, acute metabolic effects of E treatment may be balanced over time by beneficial effects on food intake and physical activity. An improved understanding of both the acute and chronic effects of HRT on metabolism, body composition, and fat distribution may be helpful for women initiating HRT.
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