Long-Term Effects of Recombinant Human Leptin (Metreleptin) on Nocturnal LH Secretion in Lipodystrophy Patients

Presentation Number: OR22-4
Date of Presentation: April 1st, 2017

Brent S. Abel*, Caroline Sedmak, Mary F. Walter, Phillip Gorden, Ranganath Muniyappa and Rebecca J. Brown
NIDDK, NIH

Abstract

Women with lipodystrophy suffer from infertility associated with hypogonadotrophic hypogonadism and hyperandrogenism (1). Treatment of lipodystrophy patients for two weeks with recombinant human leptin (metreleptin) increases nocturnal LH secretion (2). However, the long-term effects of metreleptin treatment on LH secretion in lipodystrophy patients remain unknown. Eight lipodystrophy patients (6 female, 2 generalized, 6 partial) undergoing initiation of metreleptin treatment were enrolled in a clinical trial that included assessment of LH nocturnal secretory dynamics at baseline (PRE) and 6 months (POST) after initiation. The dose of metreleptin was titrated to 9.5 ± 1.4 mg per day (mean ± SD) during the first six months to balance metabolic improvement against excessive weight loss. LH nocturnal secretory dynamics were assessed by 10 minute sampling from 23:00 to 07:00 and analyzed by multiparameter deconvolution. FSH, estradiol (E2), total testosterone (T), and sex hormone binding globulin (SHBG) were measured from samples collected at the end of each sampling. Data from baseline and 6 months were compared by paired t-test or Wilcoxon signed rank test based on normality. Neither mean (PRE: 3.3 ± 1.0 U/L, POST: 3.66 ± 1.8, p=0.63) nor integrated nocturnal LH concentrations (PRE: 1616 ± 495 U·L-1·min-1, POST: 1795 ± 889, p=0.585) were significantly different after treatment. LH burst frequency (PRE: 0.61 ± 0.26 hr-1, POST: 0.50 ± 0.31, p=0.56) and secretory burst mass (PRE: 7.6 ± 13.9 U/L, POST: 6.5 ± 4.8, p=0.30) were also similar. Consequently, neither basal secretion of LH (PRE: 18 ± 24 U·L-1·8hr-1, POST: 19 ± 7, p=0.47) nor pulsatile production rate (PRE: 34 ± 56 U·L-1·8hr-1, POST: 40 ± 19, p=0.47) changed after treatment. FSH levels were also similar (PRE: 4.4 ± 4.9 U/L, POST: 5.3 ± 4.7, p=0.16). In females, E2 (PRE: 40 ± 32 pg/mL, POST: 49 ± 33, p=0.73), T (PRE: 33 ± 19 ng/dL, POST: 34 ± 17, p=0.92), and SHBG (PRE: 12 ± 6 nmol/L, POST: 19 ± 12, p=0.09) levels did not change. These findings suggest that the stimulatory effect of leptin on the hypothalamic-pituitary-gonadal (HPG) axis is acute and does not persist long-term. Possible explanations for the differences between our observations and those changes measured after 2 weeks of metreleptin treatment include a smaller sample size, preponderance of partial lipodystrophy patients, and fewer controlled variables.

 

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