The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients.
Lipodystrophy patients are hypoleptinemic and insulin resistant. Women have enlarged polycystic ovaries, hyperandrogenism, and amenorrhea. We have determined the role of correction of hypoleptinemia on these metabolic and neuroendocrine parameters. Ten females and 4 males with generalized lipodystrophy were treated with recombinant methionyl human leptin (r-metHuLeptin) in physiologic doses in an open-labeled study for a period of 12 and 8 months, respectively. In the female group, serum free testosterone decreased from 39.6 +/- 11 to 18.9 +/- 4.5 ng/dL (P < 0.01) and serum sex hormone binding globulin increased from 14 +/- 2.5 to 25 +/- 4.8 nmol/L (P < 0.02). Luteinizing hormone (LH) responses to LH releasing hormone were more robust after therapy and significantly changed in the youngest group of 3 female patients (P < 0.01). Ovarian ultrasound showed a polycystic ovarian disease pattern in all patients and did not change after therapy. Eight of the 10 patients had amenorrhea prior to therapy and all 8 developed normal menses after therapy. In the male group, serum testosterone tended to increase from 433 +/- 110 to 725 +/- 184 ng/dL (P = 0.1) and sex hormone binding globulin also increased from 18.25 +/- 2.6 to 27 +/- 1.7 nmol/L (P < 0.04) following r-metHuLeptin therapy. Serum LH response to LH releasing hormone did not show significant changes. Five additional hypoleptinemic male subjects with minimal metabolic abnormalities underwent normal pubertal development without receiving r-metHuLeptin therapy. In both genders, insulin-like growth factor increased significantly and there were no differences in growth hormone, thyroid, or adrenal hormone levels following r-metHuLeptin therapy. Glycemic parameters significantly improved after r-metHuLeptin therapy in both groups. Hypoglycemic medications were discontinued in 7 of 12 patients and dramatically reduced in 5 patients. r-metHuLeptin therapy plays an important role in insulin sensitivity. In females, it plays an additional role in normalizing menstrual function. This is likely to occur both from increasing insulin sensitivity and from restoring LH pulsatility. The persistent hypoleptinemic state in these subjects did not inhibit pubertal development.
Musso
Carla
C
Clinical Endocrinology Branch, NIDDK, National Institute of Health, Bethesda, MD 20892-1770, USA. carlam@intra.niddk.nih.gov
Cochran
Elaine
E
Javor
Edward
E
Young
Janice
J
Depaoli
Alex M
AM
Gorden
Phillip
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D000568:Amenorrhea / Q000097:blood / Q000188:drug therapy; D000728:Androgens / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D005260:Female; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D017588:Hyperandrogenism / Q000188:drug therapy*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000031:analogs & derivatives* / Q000172:deficiency* / Q000627:therapeutic use*; D008060:Lipodystrophy / Q000097:blood / Q000188:drug therapy*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D008598:Menstruation / Q000187:drug effects*; D010901:Pituitary Function Tests; D010902:Pituitary Gland / Q000187:drug effects*; D011085:Polycystic Ovary Syndrome / Q000097:blood / Q000188:drug therapy; D011627:Puberty / Q000502:physiology; D011994:Recombinant Proteins / Q000627:therapeutic use; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood; D013961:Thyroid Gland / Q000502:physiology
D000728:Androgens; D001786:Blood Glucose; D020738:Leptin; D011994:Recombinant Proteins; D012738:Sex Hormone-Binding Globulin; C122136:recombinant methionyl human leptin; D019382:Human Growth Hormone; D013739:Testosterone; D007334:Insulin-Like Growth Factor I; D007986:Luteinizing Hormone