Effect of Leptin Replacement on Pituitary Hormone Regulation in Patients with Severe Lipodystrophy
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 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.
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Female patients generally had hypogonadotropic amenorrhea.
“Female patients generally had hypogonadotropic amenorrhea, as previously described (9,10).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [9]
Most female patients resumed and sustained normal menses following initiation of r-metHuLeptin.
“Most female patients resumed and sustained normal menses following initiation of r-metHuLeptin”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [9]
The resumption of normal menses in female patients was consistent with normalization of their gonadotropin axis.
“consistent with normalization of their gonadotropin axis (9,10).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [9]
R-MetHuLeptin therapy is associated with decreased energy intake, improvements in dyslipidemia, hepatic steatosis, and insulin resistance, as well as hypothalamic regulation of the gonadal axis.
“R-MetHuLeptin therapy is associated with decreased energy intake, improvements in dyslipidemia, hepatic steatosis, and insulin resistance, as well as hypothalamic regulation of the gonadal axis (9,10).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [9]
R-metHuLeptin therapy led to a decrease in serum androgen levels and normal cyclic menses in women of reproductive age.
“R-metHuLeptin therapy led to a decrease in serum androgen levels and normal cyclic menses in women of reproductive age (9,10).”
From Long-Term Efficacy of Leptin Replacement in Patients With Generalized Lipodystrophy (2005) · cites this paper as [9]
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- Authors
- Oral, E. A., Ruiz, E., Andewelt, A., Sebring, N., Wagner, A. J., Depaoli, A. M., & Gorden, P.
- Affiliations
- National Institutes of Health (US)
- Amgen (United States) (US)
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2002-07
- Volume
- 87
- Issue
- 7
- Pages
- 3110-3117
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2070139973
- Cited by
- 129
- References
- 27
- Citations by year
- 2025: 4 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 2 · 2019: 3 · 2018: 7 · 2017: 3 · 2016: 3 · 2015: 8 · 2014: 4 · 2013: 2 · 2012: 2
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- leptin replacement therapy, recombinant human leptin, pituitary hormone regulation, leptin deficiency, menstrual cycle restoration, TSH response to TRH, ACTH, cortisol, estradiol, thyroid function, insulin resistance, diabetes mellitus, energy homeostasis, hypothalamic-pituitary-adrenal axis
- MeSH terms
- Adolescent, Adult, Estradiol, Female, Humans, Hypothalamo-Hypophyseal System, Luteinizing Hormone, Gonadotropin-Releasing Hormone, Lipodystrophy, Menstruation, Osmolar Concentration, Ovary, Pituitary Hormones, Pituitary-Adrenal System, Prospective Studies, Recombinant Proteins, Severity of Illness Index, Testosterone, Thyroid Hormones, Ultrasonography, Leptin
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