Correspondence

Estrogen, Lipid Oxidation, and Body Fat

N Engl J Med 1995; 333:669-670September 7, 1995

Article

To the Editor:

Oral estrogen treatment is associated with weight gain and often with the perception on the patient's part of increased adiposity.1 Evidence of increased body fat is lacking, and the possible mechanism involved is not known. We report the results of a study in a tall young woman, which suggest that estrogen decreases lipid oxidation and increases body fat.

The patient was a 19-year-old woman with ovarian agenesis treated with 60, then 100, and then 200 μg of ethinyl estradiol per day, with each dose given for one month, which resulted in epiphyseal closure. Treatment with an oral contraceptive steroid containing 30 μg of ethinyl estradiol was started six months later. Indirect calorimetry2 was performed in the fasting state and nonfasting state (after a standardized mixed meal) at the end of each treatment phase. Body composition was measured by dual-energy x-ray absorptiometry2 before treatment, after the administration of 200 μg of ethinyl estradiol, and six months after the withdrawal of ethinyl estradiol.

Treatment with ethinyl estradiol resulted in a progressive, dose-dependent, but reversible decrease in lipid oxidation in the fasting and nonfasting states (Figure 1Figure 1Basal and Postprandial Carbohydrate, Lipid, and Protein Oxidation before, during, and after Treatment with Ethinyl Estradiol (60, 100, and 200 μg) and during Treatment with an Oral Contraceptive Containing 30 μg of Ethinyl Estradiol.). The dose of ethinyl estradiol was inversely correlated with basal lipid oxidation (r² = 0.92, P = 0.003) and postprandial lipid oxidation (r² = 0.7, P = 0.04). During treatment with ethinyl estradiol, the patient's body weight increased by 3.0 kg, and body fat increased by 1.6 kg (7.1 percent); both values returned to pretreatment levels after the ethinyl estradiol had been withdrawn. Fasting serum triglyceride concentrations were increased by ethinyl estradiol and were significantly related to the dose (r² = 0.83, P = 0.01) and inversely related to basal lipid oxidation (r² = 0.89, P = 0.005).

In vitro, estrogen reduces hepatic ketogenesis (a product of lipid oxidation) and increases the incorporation of fatty acids into triglycerides.3 These findings, together with clinical studies showing that oral estrogen treatment increases serum triglyceride concentrations in a dose-dependent manner,4 suggest that estrogen regulates the metabolism of hepatic fatty acids by partitioning them from oxidative into lipogenic pathways. Increases in serum triglyceride concentrations induced by estrogen may result from the intrahepatic accumulation of triglyceride caused by the suppression of lipid oxidation. Our finding of a strong inverse relation between lipid oxidation and serum triglyceride concentrations supports this notion. The effect of estrogen on hepatic fatty-acid metabolism is likely to be a first-pass pharmacologic effect, because transdermal estrogen administration has little effect on serum triglyceride concentrations4 or lipid oxidation.5 We propose that oral estrogen increases body fat by inhibiting lipid oxidation.

Anthony J. O'Sullivan, M.B., B.S.
David M. Hoffman, M.B., B.S.
Ken K.Y. Ho, M.D
Garvan Institute of Medical Research, Sydney 2010, NSW, Australia

5 References

1. 1

   Linn ES. Clinical significance of the androgenicity of progestins in hormonal therapy in women. Clin Ther 1990;12:447-455
   Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   Weinstein I, Soler-Argilaga C, Werner HV, Heimberg M. Effects of ethynyloestradiol on the metabolism of [1-¹⁴C] oleate by perfused livers and hepatocytes from female rats. Biochem J 1979;180:265-271
   Web of Science | Medline

4. 4

   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
   Full Text | Web of Science | Medline

5. 5

   Jensen MD, Martin ML, Cryer PE, Roust LR. Effects of estrogen on free fatty acid metabolism in humans. Am J Physiol 1994;266:E914-E920
   Web of Science | Medline

Citing Articles (6)

Citing Articles

1. 1

   Betty N. Wu, Anthony J. O'Sullivan. (2011) Sex Differences in Energy Metabolism Need to Be Considered with Lifestyle Modifications in Humans. Journal of Nutrition and Metabolism 2011, 1-6
   CrossRef

2. 2

   A. J. O'Sullivan. (2009) Does oestrogen allow women to store fat more efficiently? A biological advantage for fertility and gestation. Obesity Reviews 10:2, 168-177
   CrossRef

3. 3

   Rebecca Lwin, Betty Darnell, Robert Oster, Jeannine Lawrence, Jill Foster, Ricardo Azziz, Barbara A. Gower. (2008) Effect of oral estrogen on substrate utilization in postmenopausal women. Fertility and Sterility 90:4, 1275-1278
   CrossRef

4. 4

   Barbara A. Gower, Paul B. Higgins. (2003) Energy balance, body composition, and puberty in children and adolescents: importance of ethnicity. Current Opinion in Endocrinology & Diabetes 10:1, 9-22
   CrossRef

5. 5

   L Chmouliovsky, F Habicht, R.W James, T Lehmann, A Campana, A Golay. (1999) Beneficial effect of hormone replacement therapy on weight loss in obese menopausal women. Maturitas 32:3, 147-153
   CrossRef

6. 6

   Naveed Sattar, Allan Gaw, Chris J. Packard, Ian A. Greer. (1996) Potential pathogenic roles of aberrant lipoprotein and fatty acid metabolism in pre-eclampsia. BJOG: An International Journal of Obstetrics and Gynaecology 103:7, 614-620
   CrossRef