FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 351:987-997 September 2, 2004 Number 10 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Perspective by Ahima, R. S. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Disruptions in hypothalamic–gonadal and other endocrine axes due to energy deficits are associated with low levels of the adipocyte-secreted hormone leptin and may result in hypothalamic amenorrhea. We hypothesized that exogenous recombinant leptin replacement would improve reproductive and neuroendocrine function in women with hypothalamic amenorrhea.

Methods Eight women with hypothalamic amenorrhea due to strenuous exercise or low weight were studied for one month before receiving recombinant human leptin and then while receiving treatment for up to three months. Six control subjects with hypothalamic amenorrhea received no treatment and were studied for a mean (±SD) of 8.5±8.1 months.

Results Luteinizing hormone (LH) pulsatility, body weight, ovarian variables, and hormone levels did not change significantly over time in the controls and during a one-month control period before recombinant leptin therapy in the treated subjects. In contrast, recombinant leptin treatment increased mean LH levels and LH pulse frequency after two weeks and increased maximal follicular diameter, the number of dominant follicles, ovarian volume, and estradiol levels over a period of three months. Three patients had an ovulatory menstrual cycle (P<0.05 for the comparison with an expected rate of spontaneous ovulation of 10 percent); two others had preovulatory follicular development and withdrawal bleeding during treatment (P<0.05). Recombinant leptin significantly increased levels of free triiodothyronine, free thyroxine, insulin-like growth factor 1, insulin-like growth factor–binding protein 3, bone alkaline phosphatase, and osteocalcin but not cortisol, corticotropin, or urinary N-telopeptide.

Conclusions Leptin administration for the relative leptin deficiency in women with hypothalamic amenorrhea appears to improve reproductive, thyroid, and growth hormone axes and markers of bone formation, suggesting that leptin, a peripheral signal reflecting the adequacy of energy stores, is required for normal reproductive and neuroendocrine function.

Source Information

From the Reproductive Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School (C.K.W., P.S.); and the Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School (J.L.C., J.B., A.K., C.S.M.) — all in Boston; and Amgen, Thousand Oaks, Calif. (R.M., A.M.D.).

Drs. Welt and Chan contributed equally to this article.

Address reprint requests to Dr. Mantzoros at the Division of Endocrinology, Diabetes, and Metabolism, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Stoneman 816, Boston, MA 02215, or at cmantzor{at}bidmc.harvard.edu.

Full Text of this Article

Related Letters:

Recombinant Human Leptin in Women with Hypothalamic Amenorrhea
LaMarca A., Volpe A., Mantzoros C.
Extract | Full Text | PDF  
N Engl J Med 2004; 351:2343, Nov 25, 2004. Correspondence

This article has been cited by other articles:

• Van Vugt, D. A. (2009). Brain imaging studies of appetite in the context of obesity and the menstrual cycle. Hum Reprod Update 0: dmp051v1-dmp051 [Abstract] [Full Text]  
• Araujo, R. L., Andrade, B. M., da Silva, M. L., Ferreira, A. C. F., Carvalho, D. P. (2009). Tissue-specific deiodinase regulation during food restriction and low replacement dose of leptin in rats. Am. J. Physiol. Endocrinol. Metab. 296: E1157-E1163 [Abstract] [Full Text]  
• Donato, J. Jr, Silva, R. J., Sita, L. V., Lee, S., Lee, C., Lacchini, S., Bittencourt, J. C., Franci, C. R., Canteras, N. S., Elias, C. F. (2009). The Ventral Premammillary Nucleus Links Fasting-Induced Changes in Leptin Levels and Coordinated Luteinizing Hormone Secretion. J. Neurosci. 29: 5240-5250 [Abstract] [Full Text]  
• Bluher, S., Mantzoros, C. S (2009). Leptin in humans: lessons from translational research. Am. J. Clin. Nutr. 89: 991S-997S [Abstract] [Full Text]  
• Friedman, J. M (2009). Leptin at 14 y of age: an ongoing story. Am. J. Clin. Nutr. 89: 973S-979S [Abstract] [Full Text]  
• Farooqi, I S., O'Rahilly, S. (2009). Leptin: a pivotal regulator of human energy homeostasis. Am. J. Clin. Nutr. 89: 980S-984S [Abstract] [Full Text]  
• Brennan, A. M, Lee, J. H, Tsiodras, S., Chan, J. L, Doweiko, J., Chimienti, S. N, Wadhwa, S. G, Karchmer, A. W, Mantzoros, C. S (2009). r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. Eur J Endocrinol 160: 173-176 [Abstract] [Full Text]  
• Mantzoros, C. S., Rifas-Shiman, S. L., Williams, C. J., Fargnoli, J. L., Kelesidis, T., Gillman, M. W. (2009). Cord Blood Leptin and Adiponectin as Predictors of Adiposity in Children at 3 Years of Age: A Prospective Cohort Study. Pediatrics 123: 682-689 [Abstract] [Full Text]  
• Bau, A M, Ernert, A, Schenk, L, Wiegand, S, Martus, P, Gruters, A, Krude, H (2009). Is there a further acceleration in the age at onset of menarche? A cross-sectional study in 1840 school children focusing on age and bodyweight at the onset of menarche. Eur J Endocrinol 160: 107-113 [Abstract] [Full Text]  
• Misra, M., Katzman, D. K., Cord, J., Manning, S. J., Mendes, N., Herzog, D. B., Miller, K. K., Klibanski, A. (2008). Bone Metabolism in Adolescent Boys with Anorexia Nervosa. J. Clin. Endocrinol. Metab. 93: 3029-3036 [Abstract] [Full Text]  
• Wilson, P. W. F., Umpierrez, G. E. (2008). Insulin Resistance and Pubertal Changes. J. Clin. Endocrinol. Metab. 93: 2472-2473 [Full Text]  
• Chan, J. L., Williams, C. J., Raciti, P., Blakeman, J., Kelesidis, T., Kelesidis, I., Johnson, M. L., Thorner, M. O., Mantzoros, C. S. (2008). Leptin Does Not Mediate Short-Term Fasting-Induced Changes in Growth Hormone Pulsatility but Increases IGF-I in Leptin Deficiency States. J. Clin. Endocrinol. Metab. 93: 2819-2827 [Abstract] [Full Text]  
• Ahima, R. S., Lazar, M. A. (2008). Adipokines and the Peripheral and Neural Control of Energy Balance. Mol. Endocrinol. 22: 1023-1031 [Abstract] [Full Text]  
• Hwang, J. J., Chan, J. L., Ntali, G., Malkova, D., Mantzoros, C. S. (2008). Leptin Does Not Directly Regulate the Pancreatic Hormones Amylin and Pancreatic Polypeptide: Interventional studies in humans. Diabetes Care 31: 945-951 [Abstract] [Full Text]  
• Hill, J. W., Elmquist, J. K., Elias, C. F. (2008). Hypothalamic pathways linking energy balance and reproduction. Am. J. Physiol. Endocrinol. Metab. 294: E827-E832 [Abstract] [Full Text]  
• Gao, Q., Horvath, T. L. (2008). Cross-talk between estrogen and leptin signaling in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 294: E817-E826 [Abstract] [Full Text]  
• Grundberg, E., Brandstrom, H., Lam, K. C. L., Gurd, S., Ge, B., Harmsen, E., Kindmark, A., Ljunggren, O., Mallmin, H., Nilsson, O., Pastinen, T. (2008). Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells. Physiol. Genomics 33: 301-311 [Abstract] [Full Text]  
• Wilson, M. E., Kinkead, B. (2008). Gene-Environment Interactions, Not Neonatal Growth Hormone Deficiency, Time Puberty in Female Rhesus Monkeys. Biol. Reprod. 78: 736-743 [Abstract] [Full Text]  
• Chehab, F. F. (2008). Minireview: Obesity and LipOdystrophy--Where Do the Circles Intersect?. Endocrinology 149: 925-934 [Abstract] [Full Text]  
• Bermudez-Humaran, L. G., Nouaille, S., Zilberfarb, V., Corthier, G., Gruss, A., Langella, P., Issad, T. (2007). Effects of Intranasal Administration of a Leptin-Secreting Lactococcus lactis Recombinant on Food Intake, Body Weight, and Immune Response of Mice. Appl. Environ. Microbiol. 73: 5300-5307 [Abstract] [Full Text]  
• Chan, J. L., Wong, S. L., Orlova, C., Raciti, P., Mantzoros, C. S. (2007). Pharmacokinetics of Recombinant Methionyl Human Leptin after Subcutaneous Administration: Variation of Concentration-Dependent Parameters According to Assay. J. Clin. Endocrinol. Metab. 92: 2307-2311 [Abstract] [Full Text]  
• Hamrick, M. W. (2007). Leptin and Bone: A Consensus Emerging?. IBMS BoneKEy 4: 99-107 [Abstract] [Full Text]  
• Speed, C. (2007). Exercise and menstrual function. BMJ 334: 164-165 [Full Text]  
• Ahima, R. S., Qi, Y., Singhal, N. S., Jackson, M. B., Scherer, P. E. (2006). Brain Adipocytokine Action and Metabolic Regulation. Diabetes 55: S145-S154 [Abstract] [Full Text]  
• Gosman, G. G., Katcher, H. I., Legro, R. S. (2006). Obesity and the role of gut and adipose hormones in female reproduction. Hum Reprod Update 12: 585-601 [Abstract] [Full Text]  
• Ibanez, L., Ong, K., Valls, C., Marcos, M. V., Dunger, D. B., de Zegher, F. (2006). Metformin Treatment to Prevent Early Puberty in Girls with Precocious Pubarche. J. Clin. Endocrinol. Metab. 91: 2888-2891 [Abstract] [Full Text]  
• Asarian, L., Geary, N. (2006). Modulation of appetite by gonadal steroid hormones. Phil Trans R Soc B 361: 1251-1263 [Abstract] [Full Text]  
• Brauner, R., Trivin, C., Zerah, M., Souberbielle, J.-C., Doz, F., Kalifa, C., Sainte-Rose, C. (2006). Diencephalic Syndrome due to Hypothalamic Tumor: A Model of the Relationship between Weight and Puberty Onset. J. Clin. Endocrinol. Metab. 91: 2467-2473 [Abstract] [Full Text]  
• Zanker, C L, Warren, M P (2006). Regulation of reproductive function in athletic women: an investigation of the roles of energy availability and body composition * Commentary. Br. J. Sports. Med. 40: 489-490 [Full Text]  
• Ibanez, L., Valls, C., Ong, K., Dunger, D. B., de Zegher, F. (2006). Metformin Therapy during Puberty Delays Menarche, Prolongs Pubertal Growth, and Augments Adult Height: A Randomized Study in Low-Birth-Weight Girls with Early-Normal Onset of Puberty. J. Clin. Endocrinol. Metab. 91: 2068-2073 [Abstract] [Full Text]  
• Chan, J. L., Matarese, G., Shetty, G. K., Raciti, P., Kelesidis, I., Aufiero, D., De Rosa, V., Perna, F., Fontana, S., Mantzoros, C. S. (2006). Differential regulation of metabolic, neuroendocrine, and immune function by leptin in humans. Proc. Natl. Acad. Sci. USA 103: 8481-8486 [Abstract] [Full Text]  
• Pagan, Y. L., Srouji, S. S., Jimenez, Y., Emerson, A., Gill, S., Hall, J. E. (2006). Inverse Relationship between Luteinizing Hormone and Body Mass Index in Polycystic Ovarian Syndrome: Investigation of Hypothalamic and Pituitary Contributions. J. Clin. Endocrinol. Metab. 91: 1309-1316 [Abstract] [Full Text]  
• Bloomgarden, Z. T. (2006). Gut and Adipocyte Peptides. Diabetes Care 29: 450-456 [Full Text]  
• Atwood, C. W. (2005). Sleep-Related Hypoventilation: The Evolving Role of Leptin. Chest 128: 1079-1081 [Full Text]  
• Misra, M., Miller, K. K., Kuo, K., Griffin, K., Stewart, V., Hunter, E., Herzog, D. B., Klibanski, A. (2005). Secretory dynamics of leptin in adolescent girls with anorexia nervosa and healthy adolescents. Am. J. Physiol. Endocrinol. Metab. 289: E373-E381 [Abstract] [Full Text]  
• Martin, A., de Vittoris, R., David, V., Moraes, R., Begeot, M., Lafage-Proust, M.-H., Alexandre, C., Vico, L., Thomas, T. (2005). Leptin Modulates both Resorption and Formation while Preventing Disuse-Induced Bone Loss in Tail-Suspended Female Rats. Endocrinology 146: 3652-3659 [Abstract] [Full Text]  
• Knudsen, N., Laurberg, P., Rasmussen, L. B., Bulow, I., Perrild, H., Ovesen, L., Jorgensen, T. (2005). Small Differences in Thyroid Function May Be Important for Body Mass Index and the Occurrence of Obesity in the Population. J. Clin. Endocrinol. Metab. 90: 4019-4024 [Abstract] [Full Text]  
• Shea, S. A., Hilton, M. F., Orlova, C., Ayers, R. T., Mantzoros, C. S. (2005). Independent Circadian and Sleep/Wake Regulation of Adipokines and Glucose in Humans. J. Clin. Endocrinol. Metab. 90: 2537-2544 [Abstract] [Full Text]  
• Karagiannis, A., Harsoulis, F. (2005). Gonadal dysfunction in systemic diseases. Eur J Endocrinol 152: 501-513 [Abstract] [Full Text]  
• Chan, J. L., Bullen, J., Stoyneva, V., DePaoli, A. M., Addy, C., Mantzoros, C. S. (2005). Recombinant Methionyl Human Leptin Administration to Achieve High Physiologic or Pharmacologic Leptin Levels Does Not Alter Circulating Inflammatory Marker Levels in Humans with Leptin Sufficiency or Excess. J. Clin. Endocrinol. Metab. 90: 1618-1624 [Abstract] [Full Text]  
• Chan, J. L., Moschos, S. J., Bullen, J., Heist, K., Li, X., Kim, Y.-B., Kahn, B. B., Mantzoros, C. S. (2005). Recombinant Methionyl Human Leptin Administration Activates Signal Transducer and Activator of Transcription 3 Signaling in Peripheral Blood Mononuclear Cells in Vivo and Regulates Soluble Tumor Necrosis Factor-{alpha} Receptor Levels in Humans with Relative Leptin Deficiency. J. Clin. Endocrinol. Metab. 90: 1625-1631 [Abstract] [Full Text]  
• Gavrila, A., Chan, J. L., Miller, L. C., Heist, K., Yiannakouris, N., Mantzoros, C. S. (2005). Circulating Melanin-Concentrating Hormone, Agouti-Related Protein, and {alpha}-Melanocyte-Stimulating Hormone Levels in Relation to Body Composition: Alterations in Response to Food Deprivation and Recombinant Human Leptin Administration. J. Clin. Endocrinol. Metab. 90: 1047-1054 [Abstract] [Full Text]  
• Lazar, M. A. (2005). How Obesity Causes Diabetes: Not a Tall Tale. Science 307: 373-375 [Abstract] [Full Text]  
• LaMarca, A., Volpe, A., Mantzoros, C. (2004). Recombinant Human Leptin in Women with Hypothalamic Amenorrhea. NEJM 351: 2343-2343 [Full Text]  
• Seeman, E., Strewler, G. J. (2004). Clinical and Basic Research Papers - August 2004 Selections. IBMS BoneKEy 1: 1-3 [Full Text]