Impact of Bodyweight and Lifestyle on IVF Outcome

Box 1.

Deleterious Effects Described in Obese Women Undergoing IVF

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Tielemans E, van Kooij R, Looman C, Burdorf A, te Velde E, Heederik D. Paternal occupational exposures and embryo implantation rates after IVF. Fertil. Steril. 74, 690-695 (2000).
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Soares SR, Melo MA. Cigarette smoking and IVF. Expert Rev. Obstet. Gynecol. 3(4), 555-563 (2008).
Norman R, Clark A. Obesity and reproductive disorders: a review. Reprod. Fertil. Dev. 10, 55-63 (1998)
Jokela M, Kivimäki M, Elovainio M, Viikari J, Raitakari OT, Keltikangas-Järvinen L. Body mass index in adolescence and number of children in adulthood. Epidemiology 18, 599-606 (2007).
Winter E, Wang J, Davies M, Norman R. Early pregnancy loss following assisted reproductive technology treatment. Hum. Reprod. 17, 3220-3223 (2002).
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Grodstein F, Goldman MB, Cramer DW. Body mass index and ovulatory infertility. Epidemiology 5, 247-250 (1994).
The ESHRE Capri Workshop Group. Nutrition and reproduction in women. Hum. Reprod. Update 12, 193-207 (2006).
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Fedocksák P, Dale P, Storeng R et al. Impact of overweight on assisted reproduction treatment. Hum. Reprod. 11, 2523-2528 (2004).
Kelly- Weeder S, Cox CL. The impact of lifestyle risk factors on female infertility. Womens Health 44, 1-23 (2006).
Bellver J, Melo MA, Bosch E, Serra V, Remohí J, Pellicer A. Obesity and poor reproductive outcome: the potential role of the endometrium. Fertil. Steril. 88, 446-451 (2007).
• Largest study on obesity and IVF outcome with donated ova; highlights the potential role of the endometrium on the poor reproductive performance of overweight/ obese women from a clinical point of view.
Franks S. Genetic and environmental origins of obesity relevant to reproduction. Reprod. Biomed. Online 12, 526-531 (2006).
Mühlhaüsler BS. Programming of appetiteregulating neural network: a link between maternal overnutrition and the programming of obesity? J. Endocrinol. 19, 67-72 (2006).
Norman R, Noakes M, Wu R, Davies MJ, Moran L, Wang JX. Improving reproductive performance in overweight/obese women with effective weight management. Hum. Reprod. Update 10, 267-280 (2004).
•• Excellent review on weight management strategies for the improvement of reproductive performance in overweight/ obese women.
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Helsehurst N, Ells LJ, Simpson H, Batterham A, Wilkinson J, Summerbell CD. Trends in maternal obesity incidence rates, demographic predictors, and health inequalities in 36821 women over a 15.year period. BJOG 114, 187.194 (2007).
• Recent epidemiological data regarding the high and increasing prevalence of obesity in young women in developed countries.
Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Body mass index and mortality in a prospective cohort of U.S. adults. N. Engl. J. Med. 341, 1097.1105 (1999).
Bellver J, Busso C, Pellicer A, Remohi J, Simon C. Obesity and assisted reproductive technology outcomes. Reprod. Biomed. Online 12, 562.568 (2006).
Gambineri A, Pelusi C, Viccenati V, Pagotto U, Pasquali R. Obesity and polycystic ovarian syndrome. Int. J. Obes. Relat. Metab. Disord. 26, 883.896 (2002).
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Wass P, Waldenstrom U, Rossner S, Hellberg D. An android body fat distribution in females impairs the pregnancy rate of in-vitro fertilisationembryo transfer. Hum. Reprod. 12, 2057.2060 (1997).
Moran LJ, Norman RJ. The obese patient with infertility: a practical approach to diagnosis and treatment. Nutr. Clin. Care 5, 290.297 (2002).
Pasquali R, Pelusi C, Genghini S, Cacciari M, Gambineri A. Obesity and reproductive disorders in women. Hum. Reprod. Update 4, 359.372 (2003).
Budak E, Fernández M, Bellver J, Cerveró A, Simón C, Pellicer A. Interactions of the hormones leptin, ghrelin, adiponectin, resistin and PYY3-36 with the reproductive system. Fertil. Steril. 85, 1563-1581 (2006).
•• Extensive review that summarizes the effects of hormones secreted from adipose tissue and gastrointestinal tract on several reproductive functions.
Pasquali R, Gambineri A. Metabolic effects of obesity on reproduction. Reprod. Biomed. Online 12, 542-551 (2006).
Gesink Law DC, Maclehose RF, Longnecker MP. Obesity and time to pregnancy. Hum. Reprod. 22, 414-420 (2007).
Poretsky L, Cataldo NA, Rosenwaks Z, Giudice L. The insulin-related ovarian regulatory system in health and disease. Endocr. Rev. 20, 535-582 (1999).
Moschos S, Chan JL, Mantzoros CS. Leptin and reproduction: a review. Fertil. Steril. 77, 433-444 (2002).
Fertlisch K, Sator M, Gruber D, Rücklinger E, Gruber CJ, Huber JC. Body mass index, follicle-stimulating hormone and their predictive value in in vitro fertilization. J. Assist. Reprod. Genet. 12, 431-436 (2004).
van der Steeg JW, Steures P, Eijkemans MJC et al. Obesity affects spontaneous pregnancy chances in subfertile, ovulatory women. Hum. Reprod. 23, 324-328 (2008).
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Balen AH, Platteau P, Andersen AN et al. The influence of body weight on response to ovulation induction with gonadotrophins in 335 women with World Health Organization group II anovulatory infertility. BJOG 113, 1195-1202 (2006).
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Loveland JB, McClamrock HD, Malinow AM, Sharara FI. Increased body mass index has a deleterious effect on in vitro fertilization outcome. J. Assist. Reprod. Genet. 18, 382-386 (2001).
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. Assist. Reprod. Genet. 17, 547-552 (2000).
Loh S, Wang JX, Mattheus CD. The influence of body mass index, basal FSH and age on the response to gonadotrophin stimulation in non-polycystic ovarian syndrome patients. Hum. Reprod. 17, 1207-1211 (2002).
Mulders AG, Laven JS, Imani B, Eijkemans MJ, Fauser BC. IVF outcome in anovulatory infertility (WHO group 2) - including polycystic ovary syndrome - following previous unsuccessful ovulation induction. Reprod. Biomed. Online 7, 50-58 (2003).
van Swieten E, Leew-Harmsen L, Badings E, van der Linden PJQ. Obesity and clomiphene challenge test as predictors of outcome of in vitro fertilization and intracytoplasmic sperm injection. Gynecol. Obstet. Invest. 59, 220-224 (2005).
Kably-Ambe A, Barrón-Vallejo J, Limón- Luque L. Effect of body mass index and follicular synchrony in the ovarian response to ovulation induction with menotropins. Int. J. Fertil. 44, 156-159 (1999).
Carrell DT, Jones KP, Peterson CM, Aoki V, Emery BR, Campbell BR. Body mass index is inversely related to intrafollicular hCG concentrations, embryo quality and IVF outcome. Reprod. Biomed. Online 3, 109-111 (2001).
Nichols J, Crane M, Higdon H, Miller P; Boone W. Extremes of body mass index reduce in vitro fertilization pregnancy rates. Fertil. Steril. 79, 645-657 (2003).
Lashen H, Ledger W, Bernal AL, Barlow D. Extremes of body mass do not adversely affect the outcome of superovulation and in-vitro fertilization. Hum. Reprod. 14, 712.715 (1999).
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Fridstrom M, Sjoblom P, Pousette A, Hillensjo T. Serum FSH levels in women with polycystic ovary syndrome during ovulation induction using down-regulation and urofollitropin. Eur. J. Endocrinol. 136, 488.492 (1997).
Hillier SG. The Parkes lecture: controlled ovarian stimulation in women. J. Reprod. Fertil. 120, 201.210 (2000).
Imani B, Eijkemans MJ, Faessen GH, Bouchard P, Giudice LC, Fauser BC. Prediction of the follicle stimulating hormone threshold for gonadotrophin induction of ovulation in normogonadotropic anovulatory infertility: an approach to increase safety and efficiency. Fertil. Steril. 7, 83.90 (2002).
Zachow RJ, Magoffin DA. Direct intraovarian effects of leptin: impairment of synergistic action of insulin-like growth factor-I in follicle-stimulating hormonedependent estradiol-17 ƒÀ production by rat ovarian granulosa cells. Endocrinology 138, 847.850 (1997).
Agarwal SK, Vogel K, Weitsman SR, Magoffin DA. Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and teca cells of the human ovary. J. Clin. Endocrinol. Metab. 84, 1072.1076 (1999).
Fedorcsak P, Storeng R, Dale PO et al. Leptin and leptin binding activity in the preovuatory follicle of polycystic ovary syndrome patients. Scand. J. Clin. Lab. Invest. 60, 649.655 (2000).
Lewis CG, Warnes GM, Wang XJ, Matthews CD. Failure of body mass index or body weight to influence markedly the response to ovarian hyperstimulation in normal cycling women. Fertil. Steril. 53, 1097.1099 (1990).
Fedorcsak P, Storeng R, Dale PO, Tanbo T, Abyholm T. Impaired insulin action on granulosa-lutein cells in women with polycystic ovary syndrome and insulin resistance. Gynaecol. Endocrinol. 14, 327.336 (2000).
Kawamura K, Sato N, Fukuda J et al. Leptin promotes the development of mouse preimplantation embryos in vitro. Endocrinology 143, 1922-1931 (2002).
Fedorcsák P, Storeng R. Effects of leptin and leukemia inhibitory factor on preimplantation development and STAT3 signaling of mouse embryos in vitro. Biol. Reprod. 69, 1531-1538 (2003).
Castellucci M, De Matteis R, Meisser A et al. Leptin modulates extracellular matrix molecules and metalloproteinases: possible implications for trophoblast invasion. Mol. Hum. Reprod. 6, 951-958 (2000).
Alfer J, Muller-Schottle F, Cassen-Linke I et al. The endometrium as a novel target for leptin: differences in fertility and subfertility. Mol. Hum. Reprod. 6, 595-601 (2000).
Gonzalez RR, Caballero-Campo P, Jasper M et al. Leptin and leptin receptor are expressed in the human endometrium and endometrial leptin secretion is regulated by the human blastocyst. J. Clin. Endocrinol. Metab. 58, 4883-4888 (2000).
Dechaud H, Anahory T, Reyftmann L, Loup V, Hamamah S, Hedon B. Obesity does not adversely affect results in patients who are undergoing in vitro fertilization and embryo transfer. Eur. J. Obstet. Gynecol. Reprod. Biol. 127, 88-93 (2006).
Dokras A, Baredziak L, Blaine J, Syrop C, Van Voorhis BJ, Sparks A. Obstetric outcomes after in vitro fertilization in obese and morbidly obese women. Obstet. Gynecol. 108, 61-69 (2006).
Ku SY, Kim SD, Jee BC et al. Clinical efficacy of body mass index as predictor of in vitro fertilization and embryo transfer outcomes. J. Korean. Med. Sci. 21, 300-303 (2006).
Wang J, Davies M, Norman R. Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study. BMJ 321, 1320-1321 (2000).
Maheshwari A, Stofberg L, Bhattacharya S. Effect of overweight and obesity on assisted reproductive technology - a systematic review. Hum. Reprod. Update 13, 433-444 (2007).
•• Recent systematic review that shows a lower pregnancy rate and increased miscarriage rate following IVF in overweight and obese women.
Hamilton-Fairley D, Kiddy D, Watson H, Paterson C, Franks S. Association of moderate obesity with a poor pregnancy outcome in women with polycystic ovary syndrome treated with low dose gonadotrophin. BJOG 99, 128-131 (1992).
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Ramsay JE, Greer I, Sattar N. Obesity and reproduction. BMJ 333, 1159-1162 (2006).
Fedorcsak P, Storeng R, Dale P, Tanbo T, Abyholm T. Obesity is a risk factor for early pregnancy loss after IVF or ICSI. Acta Obstet. Gynecol. Scand. 79, 43-48 (2000).
Wang JX, Davies M, Norman RJ. Obesity increases the risk of spontaneous abortion during infertility treatment. Obes. Res. 10, 551-554 (2002).
Bussen S, Sütterlin M, Steck T. Endocrine abnormalities during the follicular phase in women with recurrent spontaneous abortion. Hum. Reprod. 14, 18-20 (1999).
Cano F, Garcia-Velasco JA, Millet A, Remohí J, Simón C, Pellicer A. Oocyte quality in polycystic ovaries revisited: identification of a particular subgroup of women. J. Assist. Reprod. Genet. 14, 254-261 (1997).
Wang J, Davies M, Norman R. Polycystic ovarian syndrome and the risk of spontaneous abortion following assisted reproductive technology treatment. Hum. Reprod. 16, 2606-2609 (2001).
Hall F, Neubert A. Obesity and pregnancy. Obstet. Gynaecol. Surv. 4, 253-260 (2005).
Bellver J, Pellicer A. Impact of obesity on spontaneous abortion. Am. J. Obstet. Gynecol. 190, 293-294 (2004).
Linsten A, Pasker-de Jong P, de Boer E et al. Effects of subfertility cause, moking and body weight on the success rate of IVF. Hum. Reprod. 20, 1867-1875 (2005).
Metwally M, Ong KJ, Ledger WL, Li TC. Does high body mass index increase the risk of miscarriage after spontaneous and assisted conception? A meta-analysis of the evidence. Fertil. Steril. PMID: 18068166 (2007) (Epub ahead of print).
• Recent meta-analysis that shows an increased risk of miscarriage in obese women undergoing assisted reproduction.
Orvieto R, Ben-Rafael Z, Ashkenazi J et al. Outcome of pregnancies derived from assisted reproductive technologies: IVF versus ICSI. J. Assist. Reprod. Genet. 17, 385-387 (2000).
Valbuena D, Jasper M, Remohí J, Pellicer A, Simón C. Ovarian stimulation and endometrial receptivity. Hum. Reprod. 14, 107-111 (1999).
Andreasen R, Andersen M, Schantz A. Obesity and pregnancy. Acta Obstet. Gynecol. Scand. 83, 1022-1029 (2004).
Linné Y. Effects of obesity on women’s reproduction and complications during pregnancy. Obes. Rev. 5, 137-143 (2004).
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Watkins ML, Rasmussen SA, Honein MA, Botto LD, Moore CA. Maternal obesity and risk for birth defects. Pediatrics 111, 1152-1158 (2003).
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Motjabai R. Body mass index and serum folate in childbearing age women. Eur. J. Epidemiol. 19, 1029-1036 (2004).
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Catalano PM. Management of obesity in pregnancy. Obstet. Gynecol. 109, 419-433 (2007).
•• Interesting review about the risks and management of obesity during pregnancy.
Chan CC, Ng EH, Chan MM et al. Bioavailability of hCG after intramuscular or subcutaneous injection in obese and non-obese women. Hum. Reprod. 18, 2294-2297 (2003).
Krizanovská K, Ulcová- Gallová Z, Bouse V, Rokyta C. Obesity and reproductive disorders. Sb. Lek. 103, 517-526 (2002).
Metwally M, Cutting R, Tipton A, Skull J, Ledger WL, Li TC. Effect of increased body mass index on oocyte and embryo quality in IVF patients. Reprod. Biomed. Online 15, 532-538 (2007).
Ertzeid G, Storeng R. Adverse effects of gondotrophin treatment on pre- and postimplantation development in mice. J. Reprod.Fertil. 96, 649-655 (1992).
Ertzeid G, Storeng R, Lyberg T. Treatment with gondotrophins impaired implantation and fetal development in mice. J. Assist. Reprod. Genet. 10, 286-291 (1993).
Katagiri S, Moon YS, Yuen BH. The role for the uterin insulin-like gowth factor I in early embryonic loss after superovulation in the rat. Fertil. Steril. 65, 426-36 (1996).
Horcajadas JA, Riesewijk A, Polman J et al. Effect of controlled ovarian hyperstimulation in IVF on endometrial gene expression profiles. Mol. Hum. Reprod. 11, 195-205 (2005).
Simón C, Oberyé J, Bellver J et al. Similar endometrial development in oocyte donors treated with either high- or standard-dose GnRH antagonist compared with treatment with a GnRH agonist or in natural cycles. Hum. Reprod. 20, 3318- 3327 (2005).
Jansen RP. Spontaneous abortion incidence in the treatment of infertility. Am. J. Obstet. Gynaecol. 143, 451-473 (1982).
Jensen TK, Andersson AM, Jorgensen N et al. Body mass index in relation to semen quality and reproductive hormones among 1558 Danish men. Fertil. Steril. 82, 863-870 (2004).
Koloszar S, Fejes I, Zavaczki Z, Daru J, Pal A. Effect of body weight on sperm concentration in normozoospermic males. Arch. Androl. 51, 299-304 (2005).
Nguyen RHN, Wilcox AJ, Skjaerven R, Baird D. Men’s body mass index and infertility. Hum. Reprod. 22, 2488-2493 (2007).
Ramlau-Hansen CH, Thulstrup AM, Nohr EA, Bonde JP, Sorensen TIA, Olsen J. Subfecundity in overweight and obese couples. Hum. Reprod. 22, 1634-1637 (2007).
Metwally M, Tuckerman EM, Laird SM, Ledger WL, Li TC. Impact of high body mass index on endometrial morphology and function in the peri-implantation period in women with recurrent miscarriage. Reprod. Biomed. Online 14, 328-334 (2007).
Bellver J, Rossal L, Bosch E et al. Obesity and the risk of spontaneous abortion after oocyte donation. Fertil. Steril. 79, 1136-1140 (2003).
Wattanakumtornkul S, Damario M, Hall S, Thornhill AR, Tummon IS. Body mass index and uterine receptivity in the oocyte donation model. Fertil. Steril. 80, 336-340 (2003).
Styne-Gross A, Elkind-Hirsch K, Scott R. Obesity does not impact implantation rates or pregnancy outcome in women attempting conception through oocyte donation. Fertil. Steril. 83, 1629-1634 (2005).
Tummon I, Hall S, Thornhill A, Wattanakumtornkul S, Damario M. Reply to: BMI - the fragility of fertility. Fertil. Steril. 81, 727-8 (2004).
Soares SR, Troncoso C, Bosch E et al. Age and uterine receptiveness: predicting the outcome of oocyte donation cycles. J. Clin. Endocrinol. Metab. 90, 4399- 4404 (2005).
Bellver J, Bosch E, Remohí J, Pellicer A. Evidence-based medicine is gaining momentum. Fertil. Steril. 84, 1555-1556 (2005).
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Clark AM, Ledger W, Galletley C et al. Weight loss results in significant improvement in pregnancy and ovulation rates in anovulatory obese women. Hum. Reprod. 10, 2705-2712 (1995).
Moran LJ, Norman RJ. The obese patient with infertility: a practical approach to diagnosis and treatment. Nutr. Clin. Care 5, 290-297 (2002).
Clark AM, Thornley B, Tomlinson L, Galletley C, Norman RJ. Weight loss in obese infertile women results in improvement in reproductive outcome for all forms of fertility treatment. Hum. Reprod. 13, 1502-1505 (1998).
Metwally M, Li TC, Ledger WL. The impact of obesity on female reproductive function. Obes. Rev. 8, 515-523 (2007).
Pirwany IR, Yates RW, Cameron IT, Fleming R. Effects of the insulin sensitizing drug metformin on ovarian function, follicular growth and ovulation rate in obese women with oligomenorrhoea. Hum. Reprod. 14, 2963-2968 (1999).
Harbone LR, Sattar N, Norman JE, Fleming R. Metformin and weight loss in obese women with polycystic ovary syndrome: comparison of doses. J. Clin. Endocrinol. Metab. 90, 4593-4598 (2005).
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Pasquali R, Gambineri A, Biscotti D et al. 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. 85, 2767-2774 (2000).
Maciel GA, Soares Jr JM, Alves da Motta EL, Abi Haidar M, de Lima GR, Baracat EC. Nonobese women with polycystic ovary syndrome respond better than obese women to treatment with metformin. Fertil. Steril. 81, 355-60 (2004).
Moll E, Bossuyt PM, Korevaar JC, Lambalk CB, van der Veen F. Effect of clomiphene citrate plus metformin and clomiphene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinial trial. BMJ 332, 1485 (2006).
Legro RS, Barnhart HX, Schlaff WD et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 356, 551-566 (2007).
Moll E, van der Veen F, van Wely M. The role of metformin in polycystic ovary syndrome: a systematic review. Hum. Reprod. Update 13, 527-537 (2007).
Deitel M, Stone E, Kassam HA, Wilk Ej, Sutherland DJ. Gynecologic-obstetric changes after loss of massive excess weight following bariatric surgery. J. Am. Coll. Nutr. 7, 147-153 (1988).
Bilenka B, Ben-Shlomo I, Cozacov C, Gold CH, Zohar S. Fertility, miscarriage and pregnancy after vertical banded gastroplasty operation for morbid obesity. Acta Obstet. Gynecol. Scand. 74, 42-44 (1995).
Steinbrook R. Surgery for severe obesity. N. Engl. J. Med. 350, 1454-1460 (2004).
Mehri ZO. Weight loss by bariatric surgery and subsequent fertility. Fertil. Steril. 87, 430-432 (2007).
• Literature appraisal regarding the role of bariatric surgery in the management of the morbidly obese infertile patient.
Flum DR, Salem L, Elrod JA, Dellinger EP, Cheadle A, Chan L. Early mortality among Medicare beneficiaries undergoing bariatric surgical procedures. J. Am. Med. Assoc. 294, 1903-1908 (2005).
Patel JA, Colella JJ, Esaka E, Patel NA, Thomas RL. Improvement in infertility and pregnancy outcomes after weight loss surgery. Med. Clin. North. Am. 91, 515-528 (2007).
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Five-year View

The methodology for studying the implication of lifestyle factors on IVF outcome needs to be improved. A thorough evaluation of the most important IVF outcomes, such as healthy live birth rate and neonatal characteristics, is essential. Moreover, studies should consider lifetime versus procedural timing of a lifestyle habit, as well as its quantity, frequency, duration and coexistence with other habits. Future studies should include a comparison group, consider the male lifestyle and adjust for potentially confounding factors, as those related to the ovarian stimulation procedure. They should have a longitudinal design, adequate sample sizes and a thorough follow-up. Metabolites of the substances under investigation should be analyzed throughout the procedure in order to obtain more reliable conclusions.

Future studies about psychological stress and IVF should measure plasma and follicular levels of stress hormones such as prolactin and cortisol to clarify the role of these hormonal mechanisms, and determine the neuroendocrine and physiological pathways that mediate effects on IVF outcomes.

Prospective trials analyzing the effect of under/overweight and reproduction are difficult to perform. One feasible approach is to carry out randomized trials that evaluate weight management measures and the subsequent beneficial effect on the reproductive outcome. In the field of basic research, new criteria for assessing embryos based on their morphology or on their products (e.g., by proteomics or metabolomics) could help to ascertain the negative effect of the endocrine and metabolic environment in which embryos develop in women with altered bodyweight and composition. On other hand, gene expression analysis of the endometrium using microarray technology is a promising option for correlating clinical findings regarding implantation.

Based on current findings, weight reduction through diet and exercise, and often helped by psychological support, is advisable in all obese patients. Only in refractory cases should appetite suppressants and bariatric surgery be considered. Antiobesity drugs that act on the central melacortin pathway or endocannabinoid receptor are now being developed, and perhaps the combination of several drugs could lead to effective antiobesity strategies in the future, with positive consequences for the field of reproduction. Obesity is also increasingly suffered among children. Interventions in the early life may have a great impact on adult health. Long-term follow-up of childhood obesity and the impact of early interventions for weight reduction on the adult manifestation of reproductive disease are awaited.