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Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy

Diabetes Branch (E.A.O., E.R., A.A., P.G.), National Institute of Diabetes and Digestive and Kidney Diseases, and Clinical Center (N.S.), National Institutes of Health, Bethesda, Maryland 20892; and Amgen, Inc. (A.J.W., A.M.D.), Thousand Oaks, California 91320

Address all correspondence and requests for reprints to: Phillip Gorden, M.D., Diabetes Branch, Director, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, Room 8S235A, Bethesda, Maryland 20892-1770. E-mail: . phillip_gorden{at}nih.gov

Abstract

Leptin is important in regulating energy homeostasis. Severe lipodystrophy is associated with leptin deficiency and insulin resistance, hypertriglyceridemia, and hepatic steatosis. Leptin deficiency is also associated with abnormalities of the pituitary hormones in rodent models and patients with congenital absence of leptin. We inquired whether similar abnormalities are seen in patients with lipodystrophy and whether replacement of leptin will make an impact on the regulation of pituitary hormones. Seven female patients (aged 15–42 yr, all diabetic) with lipodystrophy and serum leptin levels less than 4 mg/liter were treated with recombinant methionyl-human leptin (recombinant leptin) in physiological doses in an open-labeled study. The following parameters were evaluated before and at 4 months of leptin treatment: menstrual history, pelvic ultrasonogram, LHRH, TRH, and CRH tests. While on recombinant leptin, mean serum leptin concentration increased from 1.3 ± 0.3 mg/liter to 11.1 ± 2.5 mg/liter. Only one of five patients who had intact reproductive systems was cycling normally before leptin therapy, and all five had normal menses by the fourth month of leptin therapy. Serum E2 concentrations increased (110 ± 44 pmol/liter vs. 546 ± 247 pmol/liter, P = 0.002), serum T concentrations decreased (3.5 ± 3.0 nmol/liter vs. 1.3 ± 0.7 nmol/liter, P = 0.055), and the attenuated LH response to LHRH was corrected with therapy. Serum T₃ and free T₄ were in the normal range before leptin therapy and did not change. However, serum TSH concentrations fell from 2.2 ± 1.1 µU/ml to 1.2 ± 0.7 µU/ml (P < 0.001). The percent increase in TSH following TRH administration was similar before (560%) and at 4 months (580%) of leptin therapy. The mean nonstimulated ACTH and cortisol concentrations were, respectively, 6.0 ± 3.4 pmol/liter and 680 ± 280 nmol/liter before leptin and did not change after 4 months of therapy (4.2 ± 1.2 pmol/liter, P = 0.11 and 453 ± 142 nmol/liter, P = 0.13, respectively). The ACTH and cortisol responses to CRH stimulation were normal both before and after therapy. Leptin replacement improved menstrual abnormalities and low E2 levels and corrected the attenuated LH response to LHRH in a group of young women with lipodystrophy and leptin deficiency. These results add to the growing body of evidence that metabolic signals such as leptin play a role in neuroendocrine regulation.

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