Recombinant Human Leptin in Women with Hypothalamic Amenorrhea
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《新英格兰医药杂志》
To the Editor: Perturbations in nutritional status disrupt the complex interplay of gonadotropins and gonadal hormones that are critical for ovulation and fertility. At a teleologic level, anovulation in extremely lean women would be an appropriate compensatory mechanism to avoid the excess metabolic demands imposed by reproduction at a time when nutrient intake is insufficient.
In the study by Welt et al. (Sept. 2 issue),1 the administration of leptin was associated with an ovulatory menstrual cycle in three of eight subjects. Before therapy, these eight subjects had a mean (±SD) body-mass index (the weight in kilograms divided by the square of the height in meters) of 20.5±2.0, and a significant reduction in body weight was observed during the treatment (from 54.7±4.5 to 52.2±3.5 kg).
It has been clearly demonstrated that low maternal pregravid weight is significantly associated with adverse perinatal outcomes such as preterm delivery, low birth weight, and intrauterine growth restriction.2,3 Leptin treatment in amenorrheic lean women could restore normal menstrual function, but weight gain plus estrogen supplementation should be considered the first-choice treatment. The restoration of reproductive function before an optimal body weight has been reached in extremely lean women should not be the goal.
Antonio LaMarca, M.D.
Annibale Volpe, M.D.
University of Modena and Reggio Emilia
41100 Modena, Italy
antlamarca@libero.it
References
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.
Schieve L, Cogswell ME, Scanlon KS. Prepregnancy body mass index and pregnancy weight gain: associations with preterm delivery. Obstet Gynecol 2000;96:194-200.
Ehrenberg HM, Dierker L, Milluzzi C, Mercer BM. Low maternal weight, failure to thrive in pregnancy, and adverse pregnancy outcomes. Am J Obstet Gynecol 2003;189:1726-1730.
Dr. Mantzoros replies: Our studies1,2 have indicated that low leptin levels are responsible for the neuroendocrine abnormalities seen in states of energy deficiency in humans. The potential future therapeutic usefulness of recombinant human leptin (r-metHuLeptin), the specific subgroups of patients in whom it may be indicated, and the appropriate dose (or doses) remain to be studied further. Preliminary data, however, show that weight loss is negligible in response to low physiologic doses of r-metHuLeptin (within the range expected for placebo injections) but is substantial in response to high physiologic doses,1 as seen with other hormone-replacement therapies (e.g., thyroxine administration in patients with hypothyroidism, leading to euthyroidism or hyperthyroidism).
Although low maternal pregravid weight and poor weight gain during pregnancy have been associated with low birth weight, prematurity, and intrauterine growth restriction,3,4 all the subjects in our study were within 15 percent of ideal body weight, with the average body-mass index in the normal-risk category3,4; none became pregnant. Whether the administration of r-metHuLeptin may actually improve pregnancy outcomes among women with low pregravid weight by improving their abnormal hormone (leptin, estrogen, or growth factor) levels5 remains to be studied.
Christos Mantzoros, M.D., D.Sc.
Harvard Medical School
Boston, MA 02115
cmantzor@bidmc.harvard.edu
References
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.
Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111:1409-1421.
Schieve L, Cogswell ME, Scanlon KS, et al. Prepregnancy body mass index and pregnancy weight gain: associations with preterm delivery. Obstet Gynecol 2000;96:194-200.
Ehrenberg HM, Dierker L, Milluzzi C, Mercer BM. Low maternal weight, failure to thrive in pregnancy, and adverse pregnancy outcomes. Am J Obstet Gynecol 2003;189:1726-1730.
Christou H, Serdy S, Mantzoros CS. Leptin in relation to growth and developmental processes in the fetus. Semin Reprod Med 2002;20:123-130.
In the study by Welt et al. (Sept. 2 issue),1 the administration of leptin was associated with an ovulatory menstrual cycle in three of eight subjects. Before therapy, these eight subjects had a mean (±SD) body-mass index (the weight in kilograms divided by the square of the height in meters) of 20.5±2.0, and a significant reduction in body weight was observed during the treatment (from 54.7±4.5 to 52.2±3.5 kg).
It has been clearly demonstrated that low maternal pregravid weight is significantly associated with adverse perinatal outcomes such as preterm delivery, low birth weight, and intrauterine growth restriction.2,3 Leptin treatment in amenorrheic lean women could restore normal menstrual function, but weight gain plus estrogen supplementation should be considered the first-choice treatment. The restoration of reproductive function before an optimal body weight has been reached in extremely lean women should not be the goal.
Antonio LaMarca, M.D.
Annibale Volpe, M.D.
University of Modena and Reggio Emilia
41100 Modena, Italy
antlamarca@libero.it
References
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.
Schieve L, Cogswell ME, Scanlon KS. Prepregnancy body mass index and pregnancy weight gain: associations with preterm delivery. Obstet Gynecol 2000;96:194-200.
Ehrenberg HM, Dierker L, Milluzzi C, Mercer BM. Low maternal weight, failure to thrive in pregnancy, and adverse pregnancy outcomes. Am J Obstet Gynecol 2003;189:1726-1730.
Dr. Mantzoros replies: Our studies1,2 have indicated that low leptin levels are responsible for the neuroendocrine abnormalities seen in states of energy deficiency in humans. The potential future therapeutic usefulness of recombinant human leptin (r-metHuLeptin), the specific subgroups of patients in whom it may be indicated, and the appropriate dose (or doses) remain to be studied further. Preliminary data, however, show that weight loss is negligible in response to low physiologic doses of r-metHuLeptin (within the range expected for placebo injections) but is substantial in response to high physiologic doses,1 as seen with other hormone-replacement therapies (e.g., thyroxine administration in patients with hypothyroidism, leading to euthyroidism or hyperthyroidism).
Although low maternal pregravid weight and poor weight gain during pregnancy have been associated with low birth weight, prematurity, and intrauterine growth restriction,3,4 all the subjects in our study were within 15 percent of ideal body weight, with the average body-mass index in the normal-risk category3,4; none became pregnant. Whether the administration of r-metHuLeptin may actually improve pregnancy outcomes among women with low pregravid weight by improving their abnormal hormone (leptin, estrogen, or growth factor) levels5 remains to be studied.
Christos Mantzoros, M.D., D.Sc.
Harvard Medical School
Boston, MA 02115
cmantzor@bidmc.harvard.edu
References
Welt CK, Chan JL, Bullen J, et al. Recombinant human leptin in women with hypothalamic amenorrhea. N Engl J Med 2004;351:987-997.
Chan JL, Heist K, DePaoli AM, Veldhuis JD, Mantzoros CS. The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. J Clin Invest 2003;111:1409-1421.
Schieve L, Cogswell ME, Scanlon KS, et al. Prepregnancy body mass index and pregnancy weight gain: associations with preterm delivery. Obstet Gynecol 2000;96:194-200.
Ehrenberg HM, Dierker L, Milluzzi C, Mercer BM. Low maternal weight, failure to thrive in pregnancy, and adverse pregnancy outcomes. Am J Obstet Gynecol 2003;189:1726-1730.
Christou H, Serdy S, Mantzoros CS. Leptin in relation to growth and developmental processes in the fetus. Semin Reprod Med 2002;20:123-130.