Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy.
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 T(3) and free T(4) were in the normal range before leptin therapy and did not change. However, serum TSH concentrations fell from 2.2 +/- 1.1 microU/ml to 1.2 +/- 0.7 microU/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.
Oral
Elif Arioglu
EA
Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases/NIH, Building 10, Room 8S235A, Bethesda, MD 20892, USA.
Ruiz
Elaine
E
Andewelt
Alexa
A
Sebring
Nancy
N
Wagner
Anthony J
AJ
Depaoli
Alex M
AM
Gorden
Phillip
P
D000293:Adolescent; D000328:Adult; D004958:Estradiol / Q000097:blood; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000494:pharmacology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D020738:Leptin / Q000097:blood / Q000627:therapeutic use*; D008060:Lipodystrophy / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D007986:Luteinizing Hormone / Q000378:metabolism; D008598:Menstruation / Q000187:drug effects; D009994:Osmolar Concentration; D010053:Ovary / Q000000981:diagnostic imaging; D010907:Pituitary Hormones / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000503:physiopathology; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000627:therapeutic use; D012720:Severity of Illness Index; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood; D014463:Ultrasonography
D020738:Leptin; D010907:Pituitary Hormones; D011994:Recombinant Proteins; D013963:Thyroid Hormones; D007987:Gonadotropin-Releasing Hormone; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone