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. 2002 Apr;19(4):169–176. doi: 10.1023/A:1014889928191

Leptin Affects Pregnancy Outcome of In Vitro Fertilization and Steroidogenesis of Human Granulosa Cells

Eing-Mei Tsai 1, Cheng-Hui Yang 1, Sheng-Chung Chen 1, Yung-Hsien Liu 2, Hung-Sheng Chen 1, Shih-Cheng Hsu 1, Jau-Nan Lee 1,✉
PMCID: PMC3455655  PMID: 12036084

Abstract

Purpose: This study was to examine the serum leptin levels in the prediction of pregnancy outcomes in women receiving ovarian hyperstimulation. Effect of leptin on the steroidogenesis was evaluated for granulosa cell (GC) culture in vitro. Method: Serum levels of leptin and estradiol were measured on Day 2, the time of hCG administration and oocyte retrieval in 50 women undergoing long-course GnRH agonist ovarian hyperstimulation. The production of estrogen and progesterone in granulosa cell culture were detected after administration of leptin at the absence or presence of FSH 1 mIU. Results: Leptin levels at the time of hCG injection were significantly lower in the pregnant women than in those without pregnancy. Estradiol concentrations were not correlated with leptin levels during the time of hCG injection and oocyte retrieval. High leptin concentration suppressed both basal estradiol and progesterone productions in GC. Leptin in high doses suppressed estradiol production, but did not alter progesterone production of GC in the presence of FSH. Conclusions: Serum leptin levels may be predictive of IVF pregnancy outcome with the effect on intraovarian progesterone/estradiol ratio during the follicular phase. Significantly low serum leptin levels were noted in the pregnant women than in the nonpregnant women.

Keywords: granulosa cells, leptin, pregnancy outcome, steroidogenesis

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REFERENCES

  • 1.Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425–432. doi: 10.1038/372425a0. [DOI] [PubMed] [Google Scholar]
  • 2.Karlsson C, Lindell K, Svensson E, Bergh C, Lind P, Billig H, Carlsson LM, Carlsson B. Expression of functional leptin receptors in the human ovary. J Clin Endocrinol Metab. 1997;82:4144–4148. doi: 10.1210/jcem.82.12.4446. [DOI] [PubMed] [Google Scholar]
  • 3.Cioffi JA, Van Blerkom J, Antczak M, Shafer A, Wittmers S, Snodgrass H. The expression of leptin and its receptors in preovulatory human follicles. Mol Hum Reprod. 1997;3:467–472. doi: 10.1093/molehr/3.6.467. [DOI] [PubMed] [Google Scholar]
  • 4.Barash IA, Cheung CC, Weigle DS, Ren H, Kabigting EB, Kuijper JL, Clifton DK, Steiner RA. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996;137:3144–3147. doi: 10.1210/endo.137.7.8770941. [DOI] [PubMed] [Google Scholar]
  • 5.Hassink SG, Sheslow DV, De Lancey E, Opentanova I, Considine RV, Caro JF. Serum leptin in children with obesity: Relationship to gender and development. Pediatrics. 1996;98:201–203. [PubMed] [Google Scholar]
  • 6.Yu WH, Kimura M, Walczewska A, Karanth S, McCann SM. Role of leptin in hypothalamic-pituitary function. Proc Natl Acad Sci USA. 1997;94:1023–1028. doi: 10.1073/pnas.94.3.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.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. doi: 10.1126/science.275.5296.88. [DOI] [PubMed] [Google Scholar]
  • 8.Stock SM, Sande EM, Bremme KA. Leptin levels vary significantly during the menstrual cycle, pregnancy, and in vitro fertilization treatment: Possible relation to estradiol. Fertil Steril. 1999;72:657–662. doi: 10.1016/s0015-0282(99)00321-0. [DOI] [PubMed] [Google Scholar]
  • 9.Butzow TL, Moilanen JM, Lehtovirta M, Tuomi T, Hovatta O, Siegberg R, Nilsson CG, Apter D. Serum and follicular fluid leptin during in vitro fertilization: Relationship among leptin increase, body fat mass, and reduced ovarian response. J Clin Endocrinol Metab. 1999;84:3135–3139. doi: 10.1210/jcem.84.9.6004. [DOI] [PubMed] [Google Scholar]
  • 10.Zachow RJ, Magoffin DA. Direct intraovarian effects of leptin: Impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17ß production by rat ovarian granulosa cells. Endocrinology. 1997;138:847–850. doi: 10.1210/endo.138.2.5035. [DOI] [PubMed] [Google Scholar]
  • 11.Mantzoros CS, Cramer DW, Liberman RF, Barbieri RL. 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. doi: 10.1093/humrep/15.3.539. [DOI] [PubMed] [Google Scholar]
  • 12.Barroso G, Barrionuevo M, Rao P, Graham L, Danforth D, Huey S, Abuhamad A, Oehninger S. Vascular endothelial growth factor, nitric oxide, and leptin follicular fluid levels correlate negatively with embryo quality in IVF patients. Fertil Steril. 1999;72:1024–1026. doi: 10.1016/s0015-0282(99)00442-2. [DOI] [PubMed] [Google Scholar]
  • 13.Antczak M, Van Blerkom J. Oocyte influences on early development: The regulatory proteins leptin and STAT3 are polarized in mouse and human oocytes and differentially distributed within the cells of preimplantation stage embryo. Mol Hum Reprod. 1997;3:1067–1086. doi: 10.1093/molehr/3.12.1067. [DOI] [PubMed] [Google Scholar]
  • 14.Antczak M, Van Blerkom J. Temporal and spatial aspects of fragmentation in early human embryos: Possible effects on developmental competence and association with the differential elimination of regulatory proteins from polarized domains. Hum Reprod. 1999;14:429–447. doi: 10.1093/humrep/14.2.429. [DOI] [PubMed] [Google Scholar]
  • 15.Senaris R, Garcia-Caballero T, Casabiell X, Gallego R, Castro R, Considine RV, Dieguez C, Casanueva F. Synthesis of leptin in human placenta. Endocrinology. 1997;138:4501–4504. doi: 10.1210/endo.138.10.5573. [DOI] [PubMed] [Google Scholar]
  • 16.Henson MC, Swan KF, Levin N, O'Neil JS. Expression of placental leptin and leptin receptor transcripts in early pregnancy and at term. Obstet Gynecol. 1998;92:1020–1028. doi: 10.1016/s0029-7844(98)00299-3. [DOI] [PubMed] [Google Scholar]
  • 17.Kitawaki J, Kusuki I, Koshiba H, Tsukamoto K, Honjo H. Leptin directly stimulates aromatase activity in human luteinized granulosa cells. Mol Hum Reprod. 1999;5:708–713. doi: 10.1093/molehr/5.8.708. [DOI] [PubMed] [Google Scholar]
  • 18.Agarwal SK, Vogel K, Weitsman SR, Magoffin DA. Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogensis in granulosa cells of the human ovary. J Clin Endocrinol Metab. 1999;84:1072–1076. doi: 10.1210/jcem.84.3.5543. [DOI] [PubMed] [Google Scholar]
  • 19.Brannian JD, Zhao Y, McElroy M. Leptin inhibits gonadotrophin-stimulated granulosa cells progesterone production by antagonizing insulin action. Hum Reprod. 1999;14:1445–1448. doi: 10.1093/humrep/14.6.1445. [DOI] [PubMed] [Google Scholar]
  • 20.Adams J, Polson DW, Franks S. Prevalence of polycystic ovaries in women with anovulation and idiopathic hirsutism. Br Med J. 1986;293:355–359. doi: 10.1136/bmj.293.6543.355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Van Voorhis BJ, Dawson JD, Stovall DW, Sparks AE, Syrop CH. The effects of smoking on ovarian function and fertility during assisted reproduction cycles. Obstet Gynecol. 1996;88:785–791. doi: 10.1016/0029-7844(96)00286-4. [DOI] [PubMed] [Google Scholar]
  • 22.Mantzoros CS. The role of leptin in human obesity and disease: A review of current evidence. Ann Intern Med. 1999;130:871–881. doi: 10.7326/0003-4819-130-8-199904200-00014. [DOI] [PubMed] [Google Scholar]
  • 23.Oktay K, Briggs DA, Gosden RG. Ontogeny of folliclestimulating hormone receptor gene expression in isolated human ovarian follicles. J Clin Endocrinol Metab. 1997;82:3748–3751. doi: 10.1210/jcem.82.11.4346. [DOI] [PubMed] [Google Scholar]
  • 24.McNatty KP, Smith DM, Makris A, Osathanondh R, Ryan KJ. The microenvironment of the human antral follicle: Interrelationships among the steroid levels in antral fluid, the population of granulosa cells, and the status of oocyte in vivo and in vitro. J Clin Endocrinol Metab. 1979;49:851–860. doi: 10.1210/jcem-49-6-851. [DOI] [PubMed] [Google Scholar]
  • 25.Teirmaa T, Luukkaa V, Rouru J, Koulu M, Huupponen R. Correlation between circulating leptin and luteinizing hormone during the menstrual cycle in normal-weight women. Eur J Endocrinol. 1998;139:190–194. doi: 10.1530/eje.0.1390190. [DOI] [PubMed] [Google Scholar]
  • 26.Andersen CY. Characteristics of human follicular fluid associated with successful conception after in vitro fertilization. J Clin Endocrinol Metab. 1993;77:1227–1234. doi: 10.1210/jcem.77.5.7521343. [DOI] [PubMed] [Google Scholar]
  • 27.Seibel MM, Smith D, Dlugi AM, Levesque L. Periovulatory follicular fluid hormone levels in spontaneous human cycles. J Clin Endocrinol Metab. 1989;68:1073–1077. doi: 10.1210/jcem-68-6-1073. [DOI] [PubMed] [Google Scholar]
  • 28.Messinis IE, Milingos S, Zikopoulos K, Kollios G, Serferidis K, Lolis D. Leptin concentrations in the follicular phase of spontaneous cycles and cycles superovulated with follicle stimulating hormone. Hum Reprod. 1998;13:1152–1156. doi: 10.1093/humrep/13.5.1152. [DOI] [PubMed] [Google Scholar]
  • 29.Licinio J, Negrao AB, Mantzoros C, Kaklamani V, Wong ML, 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 USA. 1998;95:2541–2546. doi: 10.1073/pnas.95.5.2541. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.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. doi: 10.1210/endo.139.11.6297. [DOI] [PubMed] [Google Scholar]
  • 31.Spicer LJ, Francisco CC. Adipose obese gene product, leptin, inhibits bovine ovarian thecal cell steroidogensis. Biol Reprod. 1998;58:207–212. doi: 10.1095/biolreprod58.1.207. [DOI] [PubMed] [Google Scholar]
  • 32.Dechaud H, Ferron G, Anahory T, Arnal F, Humeau C, Hedon B. Obesity and assisted reproduction techniques. Contracept Fertil Sex. 1998;26:564–567. [PubMed] [Google Scholar]
  • 33.Schwartz MW, Seeley RJ. Neuroendocrine responses to starvation and weight loss. N Engl J Med. 1997;336:1802–1811. doi: 10.1056/NEJM199706193362507. [DOI] [PubMed] [Google Scholar]
  • 34.Dorn LD, Chrousos GP. The neurobiology of stress: Understanding regulation of affect during female biological transition. Semin Reprod Endocrinol. 1997;15:19–35. doi: 10.1055/s-2008-1067965. [DOI] [PubMed] [Google Scholar]
  • 35.Wynn P, Picton HM, Krapez JA, Rutherford AJ, Balen AH, Gosden RG. Pretreatment with follicle stimulating hormone promotes the numbers of human oocytes reaching metaphase II by in-vitro maturation. Hum Reprod. 1998;13:3132–3138. doi: 10.1093/humrep/13.11.3132. [DOI] [PubMed] [Google Scholar]
  • 36.Escobar-Morreale HF, Serrnao-Gotarredona J, Varela C. Circulating leptin concentrations in women with hirsutism. Fertil Steril. 1997;68:898–906. doi: 10.1016/s0015-0282(97)00336-1. [DOI] [PubMed] [Google Scholar]
  • 37.Kitawaki J, Koshiba H, Ishihara H, Kusuki I, Tsukamoto K, Honjo H. Expression of leptin receptor in human endometrium and fluctuation during the menstrual cycle. J Clin Endocrinol Metab. 2000;85:1946–1950. doi: 10.1210/jcem.85.5.6567. [DOI] [PubMed] [Google Scholar]

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