Zentralbl Gynakol 2000; 122(Heft 11): 549-555
DOI: 10.1055/s-2000-10090
Übersicht

J.A.Barth Verlag in Medizinverlage Heidelberg GmbH & Co.KG

Zur Bedeutung von Leptin für die Reproduktion

F. Nawroth, Dolores Foth, T. Schmidt, Th. Römer
  • Klinik und Poliklinik für Frauenheilkunde und Geburtshilfe der Universität zu Köln (Direktor: Prof. Dr. P. Mallmann), Funktionsbereich Gynäkologische Endokrinologie und Reproduktionsmedizin
Weitere Informationen

Publikationsverlauf

25. 5. 2000

6. 7. 2000

Publikationsdatum:
31. Dezember 2000 (online)

Zusammenfassung

Leptin wird bevorzugt von den Adipozyten synthetisiert und könnte das Bindeglied zwischen Fettgewebe und Gehirn darstellen. In bezug auf die Reproduktion könnte die Leptinresistenz insbesondere in der Pathogenese des PCO-Syndroms eine Rolle spielen. Derzeit existieren dazu aber widersprüchliche Daten, so daß weiterer Klärungsbedarf besteht. Leptin interagiert in noch nicht genau geklärtem Ausmaß mit der Steroidsynthese und besitzt Rezeptoren in zahlreichen Geweben, was auf umfangreiche lokale und endokrine Effekte schließen läßt. Seine genaue Bedeutung für die Initiierung der Pubertät bleibt derzeit ungeklärt. Gleiches gilt für erste Daten über Leptin und Endometriose sowie für die Interpretation der Hyperleptinämie in der Schwangerschaft. Klar ist, daß dieses Protein zwischen Fettgewebe und reproduktiver Funktion vermittelt. Erst weitere umfangreiche Untersuchungen können jedoch die detaillierte physiologische und pathophysiologische Rolle von Leptin in der Reproduktion klären. Derzeit besitzt die Messung von Leptinkonzentrationen noch keine praktische Bedeutung für die klinische Routine in der Reproduktionsmedizin.

Importance of leptin in reproduction

Summary

Leptin is mainly synthesized by adipocytes and might represent the connecting link between fatty tissue and brain. In reference to reproduction, leptin resistance could play a role particularly in the pathogenesis of the PCO syndrome. However, there exists at present contradictory data on this, so that further clarification is necessary. Leptin interacts with the steroid synthesis to a degree not yet precisely clarified and possesses receptors in numerous tissues, which suggests extensive local and endocrine effects. Its exact significance for the initiation of puberty still remains unknown. The same is true for first data regarding leptin and endometriosis and the interpretation of hyperleptinemia during pregnancy. It is clear that this protein mediates between fatty tissue and the reproductive function. However, the detailed physiologic and pathophysiologic role of leptin in reproduction can only be clarified through further extensive studies. To date there is not yet a practical importance for the measurement of leptin in routine work in reproductive medicine.

MeSH

C18.654.621 obesityD12.776 proteins

Literatur

  • 1 Ahima R S, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier J S. Role of leptin in the neuroendocrine response to fasting.  Nature. 1996;  382 250-252
  • 2 Alviggi C, Pisaturo M L, Carravetta C, Mollo A, Matarese G, Strina I, Lombardi L, Sanna V, De Placido G. Leptin concentrations in endometriosis.  Hum Reprod (Abstract Book 1). 2000;  15 38-39
  • 3 Behre H M, Simoni M, Nieschlag E. Strong association between serum levels of leptin and testosterone in men.  Clin Endocrinol. 1997;  47 237-240
  • 4 Bray G A, York D A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis.  Physiol Rev. 1979;  59 719-809
  • 5 Brzechffa P R, Jakimiuk A J, Agarwal S K, Weitsman S R, Buyalos R P, Magoffin D A. Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1996;  81 4166-4169
  • 6 Campfield L A, Smith F J, Guisez Y, Devos R, Burn P. Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural network.  Science. 1995;  269 546-549
  • 7 Chebab F, Lim M, Lu R. Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin.  Nat Genet. 1996;  12 318-320
  • 8 Cheung C C, Clifton D K, Steiner R A. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus.  Endocrinology. 1997;  138 4489-4492
  • 9 Cioffi J A, Van Blerkom J, Antczak M, Shafer A, Wittmer S, Snodgrass H R. The expression of leptin and its receptors in pre-ovulatory human follicles.  Mol Hum Reprod. 1997;  3 467-472
  • 10 Cohen B, Novich D, Rubinstein M. Modulation of insulin activities by leptin.  Science. 1996;  274 1185-1188
  • 11 Coleman D L. Obese and diabetes: two mutant genes causing diabetes-obesity syndrome.  Diabetologia. 1978;  14 141-148
  • 12 Considine R V, Sinha M K, Heiman M L, Kriauciunas A, Stephens T W, Nyce M R, Ohannesian J P, Marco C C, McKee L J, Bauer T L. Serum immunoreactive-leptin concentrations in normal-weight and obese humans.  N Engl J Med. 1996;  334 292-295
  • 13 Conway G S, Jacobs H S. Leptin: a hormone of reproduction.  Hum Reprod. 1997;  12 633-635
  • 14 Demerath E W, Towne B, Wisemandle W, Blangero J, Chumlea W C, Siervogel R M. Serum leptin concentration, body composition, and gonadal hormones during puberty.  Int J Obes Relat Metab Disord. 1999;  23 678-685
  • 15 Donahoo W T, Jensen D R, Yost T J, Eckel R H. Isoproterenol and somatostatin decrease plasma leptin in humans: a novel mechanism regulating leptin secretion.  Clin Endocrinol Metab. 1997;  82 4139-4143
  • 16 Erickson J C, Clegg K E, Palmiter R D. Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y.  Nature. 1996;  381 415-418
  • 17 Farooqi I S, Jebb S A, Langmack G, Lawrence E, Cheetham C H, Prentice A M, Hughes I A, Mc Camish M A, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency.  N Engl J Med. 1999;  341 879-884
  • 18 Geisthövel F, Meysing A, Brabant G. C-peptide and insulin, but not C19-steroids, support the predictive value of body mass index on leptin in serum of premenopausal women.  Hum Reprod. 1998;  13 547-553
  • 19 Gill M S, Toogood A A, O'Neill P A, Adams J E, Thorner M O, Shalet S M, Clayton P E. Relationship between growth hormone (GH) status, serum leptin and body composition in healthy and GH deficient elderly subjects.  Clin Endocrinol. 1997;  47 161-167
  • 20 Halaas J L, Gajiwala K S, Maffei M, Cohen S L, Chait B T, Rabinowitz D, Lallone R L, Burley S K, Friedman J M. Weight-reducing effects of the plasma protein encoded by the obese gen.  Science. 1995;  269 543-546
  • 21 Hardie L J, Guilhot N, Trayhorn P. Regulation of leptin production in cultured mature white adipocytes.  Horm Metab Res. 1996;  28 685-689
  • 22 Hardie L, Trayhurn P, Abramovich D, Fowler P. Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy.  Clin Endocrinol. 1997;  47 101-106
  • 23 Havel P J, Kasim-Karakas S, Dubuc G R, Mueller W, Phinney S D. Gender differences in plasma leptin concentrations.  Nat Med. 1996;  2 949-950
  • 24 Holness M J, Munns M J, Sugden M C. Current concepts concerning the role of leptin in reproductive function.  Mol Cell Endocinol. 1999;  157 11-20
  • 25 Igel M, Becker W, Herberg L, Joost H G. Hyperleptinemia, leptin resistance and polymorphic leptin receptor in the New Zealand obese mouse.  Endocrinology. 1997;  138 4234-4239
  • 26 Imani B, Eijkemans M J, de Jong F H, Payne N N, Bouchard P, Giudice L C, Fauser B C. Free androgen index and leptin are the most prominent endocrine predictors of ovarian response during clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.  J Clin Endocrinol Metab. 2000;  85 676-682
  • 27 Janik J E, Curti B D, Considine R V, Rager H C, Powers G C, Alvord W G, Smith J W, Gause B L, Kopp W C. Interleukin 1α increases serum leptin concentrations in humans.  J Clin Endocrinol Metab. 1997;  82 3084-3086
  • 28 Karlsson C, Lindell K, Svensson E, Bergh C, Lind P, Billig H, Carlsson L M, Carlsson B. Expression of functional leptin receptors in the human ovary.  J Clin Endocrinol Metab. 1997;  82 4144-4148
  • 29 Kieffer T J, Heller R S, Habener J F. Leptin receptors expressed on pancreatic beta-cells.  Biochem Biophys Res Comm. 1996;  224 522-527
  • 30 Larsson H, Ahren B. Short-term dexamethasone treatment increases plasma leptin independently of changes in insulin sensitivity in healthy women.  J Clin Endocrinol Metab. 1996;  81 4428-4432
  • 31 Lee G H, Proenca R, Montez J M, Carroll K M, Darvishzadeh J G, Lee J I, Friedman J M. Abnormal splicing of the leptin receptor in diabetic mice.  Nature. 1996;  379 632-635
  • 32 Leibowitz S F. Specificity of hypothalamic peptides in the control of behavioral and physiological processes.  Ann N Y Acad Sci. 1994;  739 12-35
  • 33 Licinio J, Mantzoros C, Negrao A B, Cizza G, Wong M L, Bongiorno P B, Chrousos G P, Karp B, Allen C, Flier J S, Gold P W. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function.  Nat Med. 1997;  3 575-579
  • 34 Licinio J, Negrao A B, Mantzoros C, Kaklamani V, Wong M L, Bongiorno P B, Mulla A, Cearnal L, Veldhuis J D, Flier J S, McCann S M, Gold P W. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women.  Proc Natl Acad Sci USA. 1998;  95 2541-2546
  • 35 Lindheim S R, Sauer M V, Carmina E, Chang P L, Zimmermann R, Lobo R A. Circulating leptin levels during ovulation induction: relation to adiposity and ovarian morphology.  Fertil Steril. 2000;  73 493-498
  • 36 Ludwig M, Klein H H, Diedrich K, Ortmann O. Serum leptin concentrations throughout the menstrual cycle.  Arch Gynecol Obstet. 2000;  263 99-101
  • 37 Luoh S, Di Marco F, Levin N, Armanini M, Xie M H, Nelson C, Bennett G L, Williams M, Spencer S A, Gurney A, de Sauvage F J. Cloning and characterization of a human leptin receptor using biologically active leptin immunoadhesin.  J Mol Endocrinol. 1997;  18 77-85
  • 38 Mantzoros C S, Moschos S, Avramopoulos I, Kaklamani V, Liolios A, Doulgerakis D E, Griveas I, Katsilambros N, Flier J S. Leptin concentrations in relation to body mass index and the tumor necrosis factor-α system in humans.  J Clin Endocrinol Metab. 1997a;  82 3408-3413
  • 39 Mantzoros C S, Dunaif A, Flier J S. Leptin concentrations in the polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997 b;  82 1687-1691
  • 40 Mantzoros C S, Cramer D W, Liberman R F, Barbieri R L. Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome.  Hum Reprod. 2000;  15 539-544
  • 41 Marti A, Berraondo B, Martinez J A. Leptin: Physiological actions.  J Physiol Biochem. 1999;  55 43-50
  • 42 Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H, Nishimura H, Yoshimasa Y, Tanaka I, Mori T, Nakao K. Nonadipose tissue production of leptin: leptin as a novel placenta-derived hormone in humans.  Nat Med. 1997;  3 1029-1033
  • 43 Matkovic V, Ilich J Z, Skugor M, Badenhop N E, Goel P, Clairmont A, Klisovic D, Nahhas R W, Landoll J D. Leptin is inversily related to age at menarche in human females.  J Clin Endocrinol Metab. 1997;  82 3239-3245
  • 44 Messinis I E, Milingos S D. Leptin in human reproduction.  Hum Reprod Update. 1999;  5 52-63
  • 45 Montague C T, Farooqi I S, Whitehead J P, Soos M A, Rau H, Wareham N J, Sewter C P, Digby J E, Mohammed S N, Hurst J A, Cheetham C H, Early A R, Barnett A H, Prins J B, O'Rahilly S. Congenital leptin deficiency is associated with severe early-onset obesity in humans.  Nature. 1997;  387 903-908
  • 46 Quinton N D, Smith R F, Clayton P E, Gill M S, Shalet S, Justice S K, Simon S A, Walters S, Postel-Vinay M C, Blakemore A I, Ross R J. Leptin binding activity changes with age: the link between leptin and puberty.  J Clin Endocrinol Metab. 1999;  84 2336-2341
  • 47 Rohner-Jeanrenaud F. A neuroendocrine reappraisal of the dual-centre hypothesis: its implications for obesity and insulin resistance.  Int J Obesity. 1995;  19 517-534
  • 48 Rosenbaum M, Nicholson M, Hirsch J, Heymsfield S B, Gallagher D, Chu F, Leibel R L. Effects of gender, body composition, and menopause on plasma concentrations of leptin.  J Clin Endocrinol Metab. 1996;  81 3424-3427
  • 49 Rouru J, Anttila L, Koskinen P, Penttila T A, Irjala K, Huupponen R, Koulu M. Serum leptin concentrations in women with polycystic ovary syndrome.  J Clin Endocrinol Metab. 1997;  82 1607-1700
  • 50 Schubring C, Blum W F, Kratzsch J, Deutscher J, Kiess W. Leptin, the ob gene product, in female health and disease.  Eur J Obstet Gynecol Reprod Biol. 2000;  88 121-127
  • 51 Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine R V, Dieguez C, Casanueva F F. Synthesis of leptin in human placenta.  Endocrinology. 1997;  138 4501-4504
  • 52 Shimizu H, Shimomura Y, Nakanishi Y, Futawatari T, Ohtani K, Sato N, Mori M. Estrogen increases in vivo leptin production in rats and human subjects.  J Endocrinol. 1997;  154 285-292
  • 53 Sinha M K, Opentanova I, Ohannesian J P, Kolaczynski J W, Heiman M L, Hale J, Becker G W, Bowsher R R, Stephens T W, Caro J F. Evidence of free and bound leptin in human circulation. Studies in lean and obese subjects and during short-term fasting.  J Clin Invest. 1996 a;  98 1277-1282
  • 54 Sinha M K, Ohannesian J P, Heiman M L, Kriauciunas A, Stephens T W, Magosin S, Marco C, Caro J F. Nocturnal rise of leptin in lean, obese and non-insulin dependent diabetes mellitus subjects.  J Clin Invest. 1996 b;  97 1344-1347
  • 55 Sir-Petermann T, Maliqueo M, Palomino A, Vantman D, Recabarren S E, Wildt L. Episodic leptin release is independent of luteinizing hormone secretion.  Hum Reprod. 1999 a;  14 2695-2699
  • 56 Sir-Petermann T, Piwonka V, Pérez F, Maliqueo M, Recabarren S E, Wildt L. Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome.  Hum Reprod. 1999 b;  14 1435-1439
  • 57 Slieker L J, Sloop K W, Surface P L, Kriauciunas A, LaQuier F, Manetta J, Bue-Valleskey J, Stephens T W. Regulation of expression of ob mRNA and protein by glucocorticoids and cAMP.  J Biol Chem. 1996;  271 5301-5304
  • 58 Stanley T G, Kyrkouli S E, Lampert S, Leibowitz S F. Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical induced of hyperphagia and obesity.  Peptides. 1986;  7 1189-1192
  • 59 Stock S M, Sande E M, Bremme K A. Leptin levels vary significantly during the menstrual cycle, pregnancy, and in vitro fertilization treatment: possible relation to estradiol.  Fertil Steril. 1999;  72 657-662
  • 60 Tartaglia L A, Dembski M, Wenig X, Deng N, Culpepper J, Devos R, Richards G J, Campfield L A, Clark F T, Deeds J, Muir C, Sanker S, Moriarty A, Moore K J, Smutko J S, Mays G G, Woolf E A, Monroe C A, Tepper R I. Identification and expression cloning of a leptin receptor, OB-R.  Cell. 1995;  83 1263-1271
  • 61 Thong F SL, Graham T E. Leptin and reproduction: Is it a critical link between adipose tissue, nutrition, and reproduction.  Can J Appl Physiol. 1999;  24 317-336
  • 62 Wabitsch M, Jensen P B, Blum W E, Christoffersen C T, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. Insulin and cortisol promote leptin production in cultured human fat cells.  Diabetes. 1996;  45 1435-1438
  • 63 Walder K, Filippis A, Clark S, Zimmet P, Collier G R. Leptin inhibits insulin binding in isolated rat adipocytes.  J Endocrinol. 1997;  155 5-7
  • 64 Weigle D S, Bukowski T R, Foster D C, Holderman S, Kramer J M, Lasser G, Lofton-Day C E, Prunkard D E, Raymond C, Kuijper J L. Recombinant ob protein reduces feeding and body weight in the ob/ob mouse.  J Clin Invest. 1995;  96 2065-2070
  • 65 Zachow R B, Magoffin D A. Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-1 on follicle-stimulating hormone dependent estradiol-17β production by rat ovarian granulosa cells.  Endocrinology. 1997;  138 847-850
  • 66 Zhang Y Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J M. Positional cloning of the mouse obese gene and its human homologue.  Nature. 1994;  372 425-432

OA Dr. med. Frank Nawroth

Universitäts-Frauenklinik Köln

Kerpener Str. 34

D-50931 Köln