Leptin and Ovarian Folliculogenesis: Implications for Ovulation Induction and ART Outcomes

John D. Brannian; Keith A. Hansen

doi:10.1055/s-2002-32501

Seminars in Reproductive Medicine, Table of Contents

Semin Reprod Med 2002; 20(2): 103-112
DOI: 10.1055/s-2002-32501

Leptin and Ovarian Folliculogenesis: Implications for Ovulation Induction and ART Outcomes

John D. Brannian, Keith A. Hansen

¹Department of Obstetrics and Gynecology, University of South Dakota School of Medicine, Sioux Falls, South Dakota

Abstract

ABSTRACT

Leptin participates in regulation of ovarian folliculogenesis indirectly via control of luteinizing hormone and follicle-stimulating hormone secretion. More recent evidence suggests that leptin also has direct regulatory actions on the developing follicle. The presence of leptin receptors on follicular cells, including oocytes, and early preimplantation embryos suggests that leptin may play a direct physiologic role in follicular maturation, oocyte development, and early cleavage. Because circulating leptin levels are directly related to body adiposity, elevated leptin concentrations associated with obesity may partly explain the negative impact of obesity on fertility. The influence of leptin on follicular development and oocyte maturation has important implications for ovulation induction and assisted reproductive technologies. Moreover, polycystic ovarian syndrome may be associated with altered leptin phsyiology.

KEYWORDS

Leptin - ovary - gonadotropin stimulation - in vitro fertilization - polycystic ovarian syndrome

Full Text

References

REFERENCES

1 Licinio J, Negrao A B, Mantzoros C. Synchronicity of frequently sampled, 24-h concentrations of circulating leptin, luteinizing hormone, and estradiol in healthy women. Proc Natl Acad Sci U S A . 1998; 95 2541-2546
2 Ruhl C E, Everhart J E. Leptin concentrations in the United States: relations with demographic and anthropometric measures. Am J Clin Nutr . 2001; 74 295-301
3 Hickey M S, Israel R G, Gardiner S N. Gender differences in serum leptin levels in humans. Biochem Molec Med . 1996; 59 1-6
4 McConway M G, Johnson D, Kelly A, Griffin D, Smith J, Wallace A M. Differences in circulating concentrations of total, free and bound leptin relate to gender and body composition in adult humans. Ann Clin Biochem . 2000; 37 717-723
5 Rosenbaum M, Nicolson M, Hirsch J. Effects of gender, body composition, and menopause on plasma concentrations of leptin. J Clin Endocr Metab . 1996; 81 3424-3427
6 Shimizu H, Shimomura Y, Nakanishi Y. Estrogen increases in vivo leptin production in rats and human subjects. J Endocr . 1997; 154 285-292
7 Casabiell X, Pineiro V, Peino R. Gender differences in both spontaneous and stimulated leptin secretion by human omental adipose tissue in vitro: dexamethasone and estradiol stimulate leptin release in women, but not in men. J Clin Endocr Metab . 1998; 83 2149-2155
8 Wu-Peng S, Rosenbaum M, Nicholson M, Chua S C, Leibel R L. Effects of exogenous gonadal steroids on leptin homeostasis in rats. Obes Res . 1999; 7 586-592
9 Menendez C, Baldelli R, Lage M. The in vitro secretion of human leptin is gender-dependent but independent of the body mass index of the donors. Eur J Endocr . 2000; 143 711-714
10 Hellstrom L, Wahrenberg H, Hruska K, Reynisdottir S, Arner P. Mechanisms behind gender differences in circulating leptin levels. J Int Med . 2000; 247 457-462
11 Elbers J M, de Roo W G, Popp-Snijders C. Effects of administration of 17beta-oestradiol on serum leptin levels in healthy postmenopausal women. Clin Endocr . 1999; 51 449-454
12 Messinis I E, Milingos S D, Alexandris E, Kariotis I, Kollios G, Seferiadis K. Leptin concentrations in normal women following bilateral ovariectomy. Hum Reprod . 1999; 14 913-918
13 Messinis I E, Kariotis I, Milingos S, Kollios G, Seferiadis K. Treatment of normal women with estradiol plus progesterone prevents the decrease of leptin concentrations induced by ovariectomy. Hum Reprod . 2000; 15 2383-2387
14 Messinis I E, Papageorgiou I, Milingos S, Asprodini E, Kollios G, Seferiadis K. Estradiol plus progesterone treatment increases serum leptin concentrations in normal women. Hum Reprod . 2001; 16 1827-1832
15 Hardie L, Trayhurn P, Abramovich D, Fowler P. Circulating leptin in women: a longitudinal study in the menstrual cycle and during pregnancy. Clin Endocr . 1997; 47 101-106
16 Lukaszuk K, Liss J, Kusiak E, Wojcikowski C. Serum leptin concentration increase during luteal phase in healthy premenopausal women. Horm Metab Res . 1998; 30 172-173
17 Riad-Gabriel M G, Jinagouda S D, Sharma A, Boyadjian R, Saad M F. Changes in plasma leptin during the menstrual cycle. Eur J Endocr . 1998; 139 528-531
18 Quinton N D, Laird S M, Okon M A. Serum leptin levels during the menstrual cycle of healthy fertile women. Br J Biomed Sci . 1999; 56 16-19
19 Cella F, Giordano G, Cordera R. Serum leptin concentrations during the menstrual cycle in normal-weight women: effects of an oral triphasic estrogen-progestin medication. Eur J Endocr . 2000; 142 174-178
20 Yamada M, Irahara M, Tezuka M, Murakami T, Shima K, Aono T. Serum leptin profiles in the normal menstrual cycles and gonadotropin treatment cycles. Gynecol Obstet Invest . 2000; 49 119-123
21 Messinis I E, Milingos S, Zikopoulos K, Kollios G, Seferiadis 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
22 Mannucci E, Ognibene A, Becorpi A. Relationship between leptin and estrogens in healthy women. Eur J Endocr . 1998; 139 198-201
23 Strowitzki T, Kellerer M, Capp E, Haring H U. Increase in serum leptin concentrations in women undergoing controlled ovarian hyperstimulation for assisted reproduction. Gynecol Endocr . 1998; 12 167-169
24 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
25 Bützow T L, Moilanen J M, Lehtovirta M. Serum and follicular fluid leptin during in vitro fertilization: relationship among leptin increase, body fat mass, and reduced ovarian response. J Clin Endocr Metab . 1999; 84 3135-3139
26 Zhao Y, Kreger D O, Brannian J D. Serum leptin concentrations in women during gonadotropin stimulation cycles. J Reprod Med . 2000; 45 121-125
27 Lindheim S R, Sauer M V, Carmina E, Chang P L, Zimmerman R, Lobo R A. Circulating leptin levels during ovulation induction: relation to adiposity and ovarian morphology. Fertil Steril . 2000; 73 493-498
28 Unkila-Kallio L, Anderson S, Koistinen H A, Karonen S-L, Ylikorkala O, Tiitinen A. Leptin during assisted reproductive cycles: the effect of ovarian stimulation and of very early pregnancy. Hum Reprod . 2001; 16 657-662
29 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
30 Löffler S, Aust G, Köhler U, Spanel-Borowski K. Evidence of leptin expression in normal and polycystic human ovaries. Mol Hum Reprod . 2001; 7 1143-1149
31 Imani B, Eijkemans M J, de Jong H F. 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 Endocr Metab . 2000; 85 676-682
32 Fedorcsak P, Storeng R, Dale P O, Tanbo T, Abyholm T. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet Gyn Scand . 2000; 79 43-48
33 Wang J X, Davies M, Norman R J. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ . 2000; 321 1320-1321
34 Lashen H, Ledger W, Bernal A L, Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization. Hum Reprod . 1999; 14 712-715
35 Wittemer C, Ohl J, Bailly M, Bettahar-Lebugle K, Nisand I. Does body mass index of infertile women have an impact on IVF procedure and outcome?. J Asst Reprod Genet . 2000; 17 547-542
36 Barroso G, Barrionuevo M, Rao P. 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
37 Van Blerkom J, Antczak M, Schrader R. The developmental potential of the human oocyte is related to the dissolved oxygen content of follicular fluid: association with vascular endothelial growth factor levels and perifollicular blood flow characteristics. Hum Reprod . 1997; 12 1047-1055
38 Manzoros 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
39 Zhao Y, Kreger D O, Brannian J D. Leptin concentrations in serum and follicular fluid during gonadotropin stimulation cycles. J Soc Gynecol Invest . 1998; 5(suppl) 50A
40 Brannian J D, Schmidt S M, Kreger D O, Hansen K A. Baseline non-fasting serum leptin concentration to body mass index ratio is predictive of IVF outcomes. Hum Reprod . 2001; 16 1819-1826
41 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 Endocr Metab . 2000; 85 1946-1950
42 Gonzalez R R, Caballero-Campo P, Jasper M. Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J Clin Endocr Metab . 2000; 85 4883-4888
43 Zamorano P L, Mahesh V B, De Sevilla M L, Chorich L P, Bhat G K, Bran D W. Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat. Neuroendocrinology . 1997; 65 223-228
44 Cioffi J A, Shafer A W, Zupancic T J. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nature Med . 1996; 2 585-589
45 Karlsson C, Lindell K, Svensson E. Expression of functional leptin receptors in the human ovary. J Clin Endocr Metab . 1997; 82 4144-4148
46 Agarwal S K, Vogel K, Weitsman S R, Magoffin D A. Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. J Clin Endocr Metab . 1999; 84 1072-1076
47 Ruiz-Cortez Z T, Men T, Palin M F, Downey B R, Lacroix D A, Murphy B D. Porcine leptin receptor: molecular structure and expression in the ovary. Mol Reprod Dev . 2000; 56 465-474
48 Matsuoka T, Tahara M, Yokoi T. Tyrosine phosphorylation of STAT3 by leptin through leptin receptor in mouse metaphase 2 stage oocyte. Biochem Biophys Res Comm . 1999; 256 480-484
49 Zachow R J, Magoffin D A. Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone-dependent estradiol-17 beta production by rat ovarian granulosa cells. Endocrinology . 1997; 138 847-850
50 Zachow R J, Weitsman S R, Magoffin D A. Leptin impairs the synergistic stimulation by transforming growth factor-β of follicle-stimulating hormone-dependent aromatase activity and messenger ribonucleic acid expression in rat ovarian granulosa cells. Biol Reprod . 1999; 61 1104-1109
51 Spicer L J, Francisco C C. The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function. Endocrinology . 1997; 138 3374-3379
52 Spicer L J, Francisco C C. Adipose obese gene product, leptin, inhibits bovine ovarian thecal cell steroidogenesis. Biol Reprod . 1998; 58 207-212
53 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
54 Brannian J D, Zhao Y, McElroy M. Leptin inhibits gonadotrophin-stimulated granulosa cell progesterone production by antagonizing insulin action. Hum Reprod . 1999; 14 1445-1448
55 Greisen S, Ledet T, Moller N. Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells. Acta Obstet Gynec Scand . 2000; 79 931-935
56 Barkan D, Jia H, Dantes A, Vardimon L, Amsterdam A, Rubinstein M. Leptin modulates the glucocorticoid-induced ovarian steroidogenesis. Endocrinology . 1999; 140 1731-1738
57 Kikuchi N, Andoh K, Abe Y, Yamada K, Mizunuma H, Ibuki Y. Inhibitory action of leptin on early follicular growth differs in immature and adult female mice. Biol Reprod . 2001; 65 66-71
58 Duggal P S, Van Der Hoek H K, Milner C R. The in vivo and in vitro effects of exogenous leptin on ovulation in the rat. Endocrinology . 2000; 141 1971-1976
59 Sierra-Honigmann M R, Nath A K, Murakami C. Biological action of leptin as an angiogenic factor. Science . 1998; 281 1683-1686
60 Bouloumie A, Drexler H C, Lafontan M, Busse R. Leptin, the product of OB gene, promotes angiogenesis. Circ Res . 1998; 83 1059-1066
61 Cao R, Brakenhielm E, Wahlestedt C, Thyberg J, Cao Y. Leptin induces vascular permeability and synergistically stimulates angiogenesis with FGF-2 and VEGF. Proc Natl Acad Sci U S A . 2001; 98 6390-6395
62 Cohen B, Barkan D, Levy Y. Leptin induces angiopoietin-2 expression in adipose tissues. J Biol Chem . 2001; 276 7697-7700
63 Bouloumie A, Marumo T, Lafontan M, Busse R. Leptin induces oxidative stress in human endothelial cells. FASEB J . 1999; 13 1231-1238
64 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 the preimplantation stage embryo. Mol Hum Reprod . 1997; 3 1067-1086
65 Takahashi Y, Okimura Y, Mizuno I. Leptin induces mitogen-activated protein kinase-dependent proliferation of C3H10T1/2 cells. J Biol Chem . 1997; 272 12897-12900
66 Swain J E, Bormann C L, Krisher R L. Effects of leptin on porcine oocyte maturation and embryo in vitro. Biol Reprod . 2001; 212
67 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
68 Vicennati V, Gambineri A, Calzoni F. Serum leptin in obese women with polycystic ovary syndrome is correlated with body weight and fat distribution but not with androgen and insulin levels. Metab Clin Exper . 1998; 47 988-992
69 El Orabi H, Ghalia A A, Khalifa A, Mahfouz H, El Shalkani A, Shoieb N. Serum leptin as an additional possible pathogenic factor in polycystic ovary syndrome. Clin Biochem . 1999; 32 71-75
70 Chapman I M, Wittert G A, Norman R J. Circulating leptin concentrations in polycystic ovary syndrome: relation to anthropometric and metabolic parameters. Clin Endocrinol . 1997; 46 175-181
71 Mantzoros C S, Dunaif A, Flier J S. Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab . 1997; 82 1687-1691
72 Laughlin G A, Morales A J, Yen S S. Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. J Clin Endocrinol Metab . 1997; 82 1692-1696
73 Rouru J, Anttila L, Koskinen P. Serum leptin concentrations in women with polycystic ovary syndrome. J Clin Endocrinol Metab . 1997; 82 1697-1700
74 Micic D, Macut D, Popovic V. Leptin levels and insulin sensitivity in obese and non-obese patients with polycystic ovary syndrome. Gynecol Endocrinol . 1997; 11 315-320
75 Gennarelli G, Holte J, Wide L, Berne C, Lithell H. Is there a role for leptin in the endocrine and metabolic aberrations of polycystic ovary syndrome?. Hum Reprod . 1998; 13 535-541
76 Kowalska I, Kinalski M, Wolczynski S, Straczkowski M, Kinalska I, Szamatowicz M. The influence of obesity on ovarian function: II. Plasma leptin concentration in women with polycystic ovary syndrome. Ginekol Polska . 1999; 70 428-432
77 Maliqueo M, Perez-Bravo F, Calvillan M, Piwonka V, Castillo T, Sir-Petermann T. Relationship between leptin and insulin sensitivity in patients with polycystic ovary syndrome. Medicina Clinica . 1999; 113 526-530
78 Clarke I, Henry B A. Leptin and reproduction. Rev Reprod . 1999; 4 48-55
79 Gonzalez R R, Simon C, Caballero-Campo P. Leptin and reproduction. Hum Reprod Update . 2000; 6 290-300
80 Caprio M, Fabbrini E, Isidori A M, Aversa A, Fabbri A. Leptin in reproduction. Trends Endocrinol Metab . 2001; 12 65-72
81 Stephens T W, Basinski M, Bristow P K. The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature . 1995; 377 530-532
82 Baranowska B, Radzikowska M, Wasilewska-Dziubinska E, Kaplinski A, Roguski K, Plonowski A. Neuropeptide Y, leptin, galanin and insulin in women with polycystic ovary syndrome. Gynecol Endocrinol . 1999; 13 344-351
83 Sir-Petermann T, Piwonka V, Perez F, Maliqueo M, Recabarren S E, Wildt L. Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?. Hum Reprod . 1999; 14 1435-149
84 Spritzer P M, Poy M, Wiltgen D, Mylius L S, Capp E. Leptin concentrations in hirsute women with polycystic ovary syndrome or idiopathic hirsutism: influence on LH and relationship with hormonal, metabolic, and anthropometric measurements. Hum Reprod . 2001; 16 1340-1346
85 Morin-Papunen L C, Koivunen R M, Thomas C, Ruokonen A, Martikainen H K. Decreased serum leptin concentrations during metformin therapy in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab . 1998; 83 2566-2568
86 Krassas G E, Kaltsas T T, Pontikides N, Jacobs H, Blum W, Messinis I. Leptin levels in women with polycystic ovary syndrome before and after treatment with diazoxide. Eur J Endocrinol . 1998; 139 184-189
87 Pasquali R, Gambineri A, Biscotti D. Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome. J Clin Endocrinol Metab . 2000; 85 2767-2774
88 Kowalska I, Kinalski M, Straczkowski M, Wolczyski S, Kinalska I. Insulin, leptin, IGF-I and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome. Eur J Endocrinol . 2001; 144 509-515