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Leptin and the Hypothalamic-Pituitary Regulation of the Gonadotropin-Gonadal Axis

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Abstract

Leptin is an adipocyte-derived protein hormone which not only conveys a signal of the amount of energy stores to the central nervous system but also plays an important role in regulating neuroendocrine function. The importance of leptin in the reproductive system has been suggested by the reproductive dysfunction associated with leptin deficiency and resistance in both animal models and humans as well as the ability of leptin to accelerate the onset of reproductive function in normal mice. Transgenic mice overexpressing leptin also have accelerated puberty, and leptin administration reverses the fasting-induced suppression of sexual maturation in rodents, indicating that leptin may serve as the critical link between sufficient energy stores and proper functioning of the reproductive system. Normal women have a pulsatile release pattern of leptin that is significantly associated with the variations in luteinizing hormone (LH) and estradiol levels. In various animal models, leptin administration restores the LH pulsatility pattern which is suppressed during fasting, indicating a hypothalamic site of action since LH pulsatility is under the control of gonadotropin-releasing hormone (GnRH). In humans, leptin has been administered to a 9-year-old leptin-deficient girl, resulting in a gonadotropin secretory pattern consistent with early puberty. While in vitro experiments with hypothalamic explants and a GnRH-secreting neuronal cell line have shown that leptin can directly stimulate GnRH secretion, the lack of leptin receptors on GnRH neurons suggests that leptin may act through other hypothalamic neuropeptides. Several neuropeptides which act as downstream effectors of leptin have been investigated, and recent studies indicate that cocaine and amphetamine-regulated transcript may be such a mediator of leptin's effect on GnRH. Leptin receptors have also been identified in human pituitaries, and leptin may influence LH release from the pituitary. However, the current evidence is conflicting, and further studies are needed in order to clarify leptin's role at the level of the pituitary. Thus, accumulating evidence suggests that leptin can regulate gonadotropin levels, and its secretion may, in turn, be influenced by GnRH or gonadal steroids but appears to be independent of LH control.

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References

  1. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman J. Positional cloning of the obese gene and its human homologue. Nature 1994;372:425–432.

    Google Scholar 

  2. Flier JS. Leptin expression and action: new experimental paradigms. Proc Natl Acad Sci 1997;94:4242–4245.

    Google Scholar 

  3. Mantzoros CS. The role of leptin in human obesity and disease: A review of current evidence. Ann Intern Med 1999; 130:671–680.

    Google Scholar 

  4. Licinio J, Mantzoros C, Negrao AB, Cizza G, Wong ML, Bongiorno PB, Chrousos GP, Karp B, Allen C, Flier JS, Gold PW. Human leptin levels are pulsatile and inversely related to pituitary-adrenal function. Nat Med 1997;3:575–579.

    Google Scholar 

  5. Sinha MK, Ohannesian JP, Heiman ML, Kriauciunas A, Stephens TW, Magosin S, Marco C, Caro JF. Nocturnal rise of leptin in lean, obese, and non-insulin-dependent diabetes mellitus subjects.J Clin Invest 1996;97:1344–1347.

    Google Scholar 

  6. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL, Caro JF. Serum immunoreactive leptin concentrations in normal-weight and obese humans. N Engl J Med 1996;334:292–295.

    Google Scholar 

  7. Boden G, Chen X, Mozzoli M, Ryan I. Effect of fasting on serum leptin in normal human subjects. J Clin Endocrinol Metab 1996;81:3419–3423.

    Google Scholar 

  8. Kolaczyncki JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effect of insulin on leptin production in humans. Diabetes 1996;45:699–701.

    Google Scholar 

  9. Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong M, Bongiorno PB, Mulla A, Cearnal L, Veldhuis JD, Flier JS, McCann SM, Gold PW. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women. Proc Natl Acad Sci 1998;95:2541–2546.

    Google Scholar 

  10. Saad MF, Damani S, Gingerich RL, Riad-Gabriel MG, Khan A, Boyadjian R, Jinagouda SD, El-Tawil K, Rude RK, Kamdar V. Sexual dimorphism in plasma leptin concentrations. J Clin Endocrinol Metab 1997;82:579–584.

    Google Scholar 

  11. Rosenbaum M, Nicolson M, Hirsch J, Heymsfield SB, Gallagher D, Chu F, Leibel R. Effects of gender, body composition, and menopause on plasma concentrations of leptin.JClin Endocrinol Metab 1996;81:3424–3427.

    Google Scholar 

  12. Woods AJ, Stock MJ. Leptin activation in hypothalamus. Nature 1996;381:745.

    Google Scholar 

  13. Ingalls AM, Dickie MM, Snell GD. Obese, a new mutation in the house mouse. J Hered 1950;41:317–318.

    Google Scholar 

  14. Johnson LM, Sidman RL. A reproductive endocrine profile in the diabetes (db) mutant mouse. Biol Reprod 1979;20: 552–559.

    Google Scholar 

  15. Saiduddin S, Bray GA, York DA, Swerdloff RS. Reproductive function in the genetically obese “fatty” rat. Endocrinology 1973;92:1251–1256.

    Google Scholar 

  16. Chehab FF, Lim ME, 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.

    Google Scholar 

  17. Mounzih K, Lu R, Chehab FF. Leptin treatment rescues the sterility of genetically obese ob/ob males. Endocrinology 1997;138:1190–1193.

    Google Scholar 

  18. Ioffe E, Moon B, Connolly E, Friedman JM. Abnormal regulation of the leptin gene in the pathogenesis of obesity. Proc Natl Acad Sci 1998;95:11852–11857.

    Google Scholar 

  19. Strobel A, Issad T, Camoin L, Ozata M, Strosberg AD. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat Genet 1998;18:213–215.

    Google Scholar 

  20. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte J, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy-Grand B. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 1998;392:398–401.

    Google Scholar 

  21. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O'Rahilly S. Congenital leptin de~ciency is associated with severe early-onset obesity in humans.Nature 1997;387:903–908.

    Google Scholar 

  22. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM, Hughes IA, McCamish MA, O'Rahilly S. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879–884.

    Google Scholar 

  23. Yura A, Ogawa Y, Sagawa N, Masuzaki H, Itoh H, Ebihara K, Aizawa-Abe M, Fujii S, Nakao K. Accelerated puberty and late-onset hypothalamic hypogonadism in female transgenic skinny mice overexpressing leptin.J Clin Invest 2000; 105:749–755.

    Google Scholar 

  24. Chehab FF, Mounzih K, Lu R, Lim ME.Early onset of reproductive function in normal female mice treated with leptin. Science 1997;275:88–90.

    Google Scholar 

  25. Ahima RS, Dushay J, Flier SN, Prabakaran D, Flier JS. Leptin accelerates the onset of puberty in normal female mice. J Clin Invest 1997;99:391–395.

    Google Scholar 

  26. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS. Role of leptin in the neuroendocrine response to fasting. Nature 1996;382:250–252.

    Google Scholar 

  27. Gruaz NM, Lalaoui M, Pierroz DD, Englaro P, Sizonenko PC, Blum WF, Aubert ML. Chronic administration of leptin into the lateral ventricle induces sexual maturation in severely food-restricted female rats. J Neuroendocrinol 1998; 10:627–633.

    Google Scholar 

  28. Carro E, Pinilla L, Seoane LM, Considine RV, Auilar E, Casanueva FF, Dieguez C. Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats. Neuroendocrinology 1997;66:375–377.

    Google Scholar 

  29. Gonzalez LC, Pinilla L, Tena-Sempere M, Dieguez C, Casanueva FF, Auilar E. Effect of acute immunoneutralization of endogenous leptin on prolactin and LH secretion during the afternoon of pro-oestrus or in steroid-treated ovariectomized female rats. J Reprod Fertil 2000;118:39–45.

    Google Scholar 

  30. Andreelli F, Hanaire-Broutin H, Laville M, Tauber JP, Riou JP, Thivolet C. Normal reproductive function in leptinde~ cient patients with lipoatropic diabetes. J Clin Endocrinol Metab 2000;85:715–719.

    Google Scholar 

  31. Burks DJ, Font de Mora J, Schubert M, Withers DJ, Myers MG, Towery HH, Altamuro SL, Flint CL, White MW. IRS-2 pathways integrate female reproduction and energy homeostasis. Nature 2000;407:377–382.

    Google Scholar 

  32. Chehab FF. Leptin as a regulator of adipose mass and reproduction. Trends Pharmacol Sci 2000;21:309–314.

    Google Scholar 

  33. Sir-Petermann T, Maliqueo M, Palomino A, Vantman D, Recabarren SE, Wildt L. Episodic leptin release is independent of luteinizing hormone secretion. Hum Reprod 1999;14: 2695–2699.

    Google Scholar 

  34. Nagatani S, Guthikonda P, Thompson RC, Tsukamura H, Maeda K, Foster DL. Evidence for GnRH regulation by leptin: leptin administration prevents reduced pulsatile LH secretion during fasting. Neuroendocrinology 1998;67: 370–376.

    Google Scholar 

  35. Kohsaka A, Watanobe H, Kakizaki Y, Habu S, Suda T.A significant role of leptin in the generation of steroid-induced luteinizing hormone and prolactin surges in female rats. Biochem Biophys Res Commun 1999;254(3):578–581.

    Google Scholar 

  36. Gonzalez LC, Pinilla L, Tena-Sempere M, Aguilar E. Leptin 116;v–130 stimulates prolactin and luteinizing hormone secretion in fasted adult male rats. Neuroendocrinology 1999; 70:213–220.

    Google Scholar 

  37. Nagatani S, Zeng Y, Keisler DH, Foster DL, Jaffe CA. Leptin regulates pulsatile luteinizing hormone and growth hormone secretion in the sheep. Endocrinology 2000;141: 3965–3975.

    Google Scholar 

  38. Dearth RK, Hiney JK, Dees WL. Leptin acts centrally to induce the prepubertal secretion of luteinizing hormone in the female rat. Peptides 2000;21:387–392.

    Google Scholar 

  39. Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci 1997;94:1023–1028.

    Google Scholar 

  40. Yu WH, Walczewska A, Karanth S, McCann SM.Nitric oxide mediates leptin-induced luteinizing hormone-releasing hormone (LHRH) and LHRH and leptin-induced LH release from the pituitary gland. Endocrinology 1997;138: 5055–5058.

    Google Scholar 

  41. Magni P, Vettor R, Pagano C, Calcagno A, Beretta E, Messi E, Zanisi M, Martini L, Motta M. Expression of a leptin receptor in immortalized gonadotropin-releasing hormonesecreting neurons. Endocrinology 1999;140:1581–1585.

    Google Scholar 

  42. Hakansson ML, Brown H, Ghilardi N, Skoda RC, Meister B. Leptin receptor immunoreactivity in chemically de~ned target neurons of the hypothalamus. J Neurosci 1998;18: 559–572.

    Google Scholar 

  43. Finn PD, Cunningham MJ, Pau KY, Spies HG, Clifton DK, Steiner RA. The stimulatory effect of leptin on the neuroendocrine reproductive axis of the monkey. Endocrinology 1998;139:4652–4662.

    Google Scholar 

  44. Cunningham MJ, Clifton DK, Steiner RA. Leptin's actions on the reproductive axis: perspectives and mechanisms. Biol Reproduct 1999;60:216–222.

    Google Scholar 

  45. Argiolas A, Melis MR, Murgia S, Schioth HB. ACTH-and alpha-MSH-induced grooming, stretching, yawning, and penile erection in male rats: Site of action in the brain and role of melanocortin receptors. Brain Res Bull 2000;51: 425–431.

    Google Scholar 

  46. Hohmann JG, Teal TH, Clifton DK, Davis J, Hruby VJ, Han G, Steiner RA. Differential role of melanocortins in mediating leptin's central effects on feeding and reproduction. Am J Physiol Regul Integr Comp Physiol 2000 278(1): R50–59.

    Google Scholar 

  47. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeir LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997;88:131–141.

    Google Scholar 

  48. Erickson JC, Ahima RS, Hollopeter G, Flier JS, Palmiter RD. Endocrine function of neuropeptide Y knockout mice. Regul Pept 1997;70:199–202.

    Google Scholar 

  49. Lebrethon MC, Vandersmissen E, Gerard A, Parent AS, Junien JL, Bourguignon JP. In vitro stimulation of the prepubertal rat gonadotropin-releasing hormone pulse generator by leptin and neuropeptide Y through distinct mechanisms. Endocrinology 2000;141:1464–1469.

    Google Scholar 

  50. Lebrethon MC, Vandersmissen E, Gerard A, Parent AS, Bourguignon JP. Cocaine and amphetamine-regulated transcript peptide mediation of leptin stimulatory effect on the rat gonadotropin-releasing hormone pulse generator in vitro. J Neuroendocrinol 2000;12:383–385.

    Google Scholar 

  51. Parent AS, Lebrethon MC, Gerard A, Vandersmissen E, Bourguignon JP. Leptin effects on pulsatile gonadotropin releasing hormone secretion from the adult rat hypothalamus and interaction with cocaine and amphetamine regulated transcript peptide and neuropeptide Y. Regul Pept 2000;92:17–24.

    Google Scholar 

  52. Jin L, Burguera BG, Couce ME, Scheithauer BW, Lamsan J, Eberhardt NL, Kulig E, Lloyd RV. Leptin and leptin receptor expression in normal and neoplastic human pituitary: Evidence of a regulatory role for leptin on pituitary cell proliferation. J Clin Endocrinol Metab 1999;84:2903–2911.

    Google Scholar 

  53. Dieterich KD, Lehnert H. Expression of leptin receptor mRNA and the long form splice variant in human anterior pituitary and pituitary adenoma. Exp Clin Endocrinol Diabetes 1998;106:522–525.

    Google Scholar 

  54. Shimon I, Yan X, Magoffin DA, Friedman TC, Melmed S. Intact leptin receptor is selectively expressed in human fetal pituitary and pituitary adenomas and signals human fetal pituitary growth hormone secretion. J Clin Endocrinol Metab 1998;83:4059–4064.

    Google Scholar 

  55. Jin L, Zhang S, Burguera BG, Couce ME, Osamura RY, Kulig E, Lloyd RV. Leptin and leptin receptor expression in rat and mouse pituitary cells. Endocrinology 2000;141:333–339.

    Google Scholar 

  56. Iqbal J, Pompolo S, Considine RV, Clarke IJ.Localization of leptin receptor-like immunoreactivity in the corticotropes, somatotropes, and gonadotropes in the ovine anterior pituitary. Endocrinology 2000;141:1515–1520.

    Google Scholar 

  57. Vidal S. Cohen SM, Horvath E, Kovacs K, Scheithauer BW, Burguera BG, Lloyd RV. Subcellular localization of leptin in non-tumorous and adenomatous human pituitaries: An immuno-ultrastructural study. J Histochem Cytochem 2000; 48:1147–1152.

    Google Scholar 

  58. Tena-Sempere M, Pinilla L, Gonzalez LC, Dieguez C, Casanueva FF, Aguilar E. Leptin inhibits testosterone secretion from adult rat testis in vitro. J Endocrinol 1999;161:211–218.

    Google Scholar 

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  1. Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA

    Jean L. Chan & Christos S. Mantzoros

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  1. Jean L. Chan
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Chan, J.L., Mantzoros, C.S. Leptin and the Hypothalamic-Pituitary Regulation of the Gonadotropin-Gonadal Axis. Pituitary 4, 87–92 (2001). https://doi.org/10.1023/A:1012947113197

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