Abstract
Infertility is defined as a failure to conceive after 12 months of unprotected intercourse. Due to the declining fertility with increasing age, couples in which the female partner age is older than 35 years may be considered as infertile after 6 months of unprotected intercourse. Irrespectively from a previous diagnosis of PCOS, the evaluation of infertility should focus on the couple and not solely on the female partner. In fact, even if one of the main cause of infertility include ovulatory dysfunction, some couples may be affected by tubal and uterine factors, endometriosis, male factor, and unexplained infertility. Infertility investigation is usually performed after a year of infertility, although earlier evaluation should be offered to those with known conditions related to subfertility. In women with PCOS, the main contributing factor for the infertility is anovulation, but several additional factors may play a role. This chapter discusses factors leading to anovulation in women with PCOS and additional characteristics of PCOS women that may affect their fertility potential.
Keywords
- Polycystic Ovary Syndrome (PCOS)
- PCOS Women
- Sex Hormone Binding Globulin (SHBG)
- Epithelial Na+ Channel (ENaC)
- Late-onset Congenital Adrenal Hyperplasia
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
References
Practice Committee of American Society for Reproductive Medicine. Definitions of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril. 2013;99:63.
Wang X, et al. Conception, early pregnancy loss, and time to clinical pregnancy: a population-based prospective study. Fertil Steril. 2003;79:577–84.
Gnoth C, et al. Time to pregnancy: results of the German prospective study and impact on the management of infertility. Hum Reprod. 2003;18:1959–66.
Gnoth C, et al. Definition and prevalence of subfertility and infertility. Hum Reprod. 2005;20:1144–7.
Evers JL. Female subfertility. Lancet. 2002;360:151–9.
WHO. Recent advances in medically assisted conception. Report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1992;820:1–111.
Hull MG, et al. Population study of causes, treatment, and outcome of infertility. Br Med J (Clin Res Ed). 1985;291:1693–7.
Templeton A, Fraser C, Thompson B. The epidemiology of infertility in Aberdeen. BMJ. 1990;301:148–52.
Bhattacharya S, et al. The epidemiology of infertility in the North East of Scotland. Hum Reprod. 2009;24:3096–107.
Miller JH, et al. The pattern of infertility diagnoses in women of advanced reproductive age. Am J Obstet Gynecol. 1999;181:952–7.
McGovern PG, et al. Utility of screening for other causes of infertility in women with “known” polycystic ovary syndrome. Fertil Steril. 2007;87:442–4.
Azziz R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab. 2004;89:2745–9.
Ehrmann DA. Polycystic ovary syndrome. N Engl J Med. 2005;352:1223–36.
Cedars MI, et al. Long-term administration of gonadotropin-releasing hormone agonist and dexamethasone: assessment of the adrenal role in ovarian dysfunction. Fertil Steril. 1992;57:495–500.
Kumar A, et al. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf). 2005;62:644–9.
Baskind NE, Balen AH. Hypothalamic-pituitary, ovarian and adrenal contributions to polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2016;37:80–97.
Yildiz BO, Azziz R. The adrenal and polycystic ovary syndrome. Rev Endocr Metab Disord. 2007;8:331–42.
Baptiste CG, et al. Insulin and hyperandrogenism in women with polycystic ovary syndrome. J Steroid Biochem Mol Biol. 2010;122:42–52.
Hendriks ML, et al. LH as a diagnostic criterion for polycystic ovary syndrome in patients with WHO II oligo/amenorrhoea. Reprod Biomed Online. 2008;16:765–71.
Rice S, et al. Stage-specific expression of androgen receptor, follicle-stimulating hormone receptor, and anti-Mullerian hormone type II receptor in single, isolated, human preantral follicles: relevance to polycystic ovaries. J Clin Endocrinol Metab. 2007;92:1034–40.
Willis DS, et al. Premature response to luteinizing hormone of granulosa cells from anovulatory women with polycystic ovary syndrome: relevance to mechanism of anovulation. J Clin Endocrinol Metab. 1998;83:3984–91.
Hugues JN, Durnerin IC. Impact of androgens on fertility–physiological, clinical and therapeutic aspects. Reprod Biomed Online. 2005;11:570–80.
Qu J, et al. Insulin resistance directly contributes to androgenic potential within ovarian theca cells. Fertil Steril. 2009;91(5 Suppl):1990–7.
Cupisti S, et al. Body mass index and ovarian function are associated with endocrine and metabolic abnormalities in women with hyperandrogenic syndrome. Eur J Endocrinol. 2008;158:711–9.
Doi SA. Neuroendocrine dysfunction in PCOS: a critique of recent reviews. Clin Med Res. 2008;6:47–53.
Strauss 3rd JF. Some new thoughts on the pathophysiology and genetics of polycystic ovary syndrome. Ann N Y Acad Sci. 2003;997:42–8.
Harlan WR, et al. Secular trends in body mass in the United States, 1960–1980. Am J Epidemiol. 1988;128:1065–74.
Kuczmarski RJ, et al. Increasing prevalence of overweight among US adults. The National Health and Nutrition Examination Surveys, 1960 to 1991. JAMA. 1994;272:205–11.
Flegal KM, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA. 2002;288:1723–7.
Flegal KM, et al. Prevalence and trends in obesity among US adults, 1999–2008. JAMA. 2010;303:235–41.
Ford ES. Prevalence of the metabolic syndrome in US populations. Endocrinol Metab Clin North Am. 2004;33:333–50.
Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman’s long-term health using data linkage. J Clin Endocrinol Metab. 2015;100:911–9.
Pasquali R, et al. Obesity and reproductive disorders in women. Hum Reprod Update. 2003;9:359–72.
Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:162–8.
Alvarez-Blasco F, et al. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med. 2006;166:2081–6.
Gambineri A, et al. Obesity and the polycystic ovary syndrome. Int J Obes Relat Metab Disord. 2002;26:883–96.
Galtier-Dereure F, et al. Choice of stimulation in polycystic ovarian syndrome: the influence of obesity. Hum Reprod. 1997;12:88–96.
White DM, et al. Induction of ovulation with low-dose gonadotropins in polycystic ovary syndrome: an analysis of 109 pregnancies in 225 women. J Clin Endocrinol Metab. 1996;81:3821–4.
Fedorcsak P, et al. The impact of obesity and insulin resistance on the outcome of IVF or ICSI in women with polycystic ovarian syndrome. Hum Reprod. 2001;16:1086–91.
Glass AR, et al. Low serum testosterone and sex-hormone-binding-globulin in massively obese men. J Clin Endocrinol Metab. 1977;45:1211–9.
Stefan N, Schick F, Haring HU. Sex hormone-binding globulin and risk of type 2 diabetes. N Engl J Med. 2009;361:2675–6. author reply 2677–8
Peter A, et al. Relationships of circulating sex hormone-binding globulin with metabolic traits in humans. Diabetes. 2010;59:3167–73.
Pasquali R, Vicennati V, and U Pagotto, Endocrine determinants of fat distribution, in Handbook of obesity, Bouchard C. Bray GA, Editor. 2003, . Marcel Dekker: New York. p. 671–692.
Kirschner MA, et al. Androgen-estrogen metabolism in women with upper body versus lower body obesity. J Clin Endocrinol Metab. 1990;70:473–9.
Simo R, et al. Novel insights in SHBG regulation and clinical implications. Trends Endocrinol Metab. 2015;26:376–83.
de Mendonca-Louzeiro MR, Annichino-Bizzacchi JM, Benetti-Pinto CL. Android fat distribution affects some hemostatic parameters in women with polycystic ovary syndrome compared with healthy control subjects matched for age and body mass index. Fertil Steril. 2015;104:467–73.
Barber TM, et al. Obesity and polycystic ovary syndrome. Clin Endocrinol (Oxf). 2006;65:137–45.
Houjeghani S, Pourghassem Gargari B, Farzadi L. Serum leptin and ghrelin levels in women with polycystic ovary syndrome: correlation with anthropometric, metabolic, and endocrine parameters. Int J Fertil Steril. 2012;6:117–26.
Pehlivanov B, Mitkov M. Serum leptin levels correlate with clinical and biochemical indices of insulin resistance in women with polycystic ovary syndrome. Eur J Contracept Reprod Health Care. 2009;14:153–9.
Chen X, et al. Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. J Mol Endocrinol. 2013;50:R21–37.
Mantzoros CS, Dunaif A, Flier JS. Leptin concentrations in the polycystic ovary syndrome. J Clin Endocrinol Metab. 1997;82:1687–91.
Budak E, et al. Interactions of the hormones leptin, ghrelin, adiponectin, resistin, and PYY3–36 with the reproductive system. Fertil Steril. 2006;85:1563–81.
Barash IA, et al. Leptin is a metabolic signal to the reproductive system. Endocrinology. 1996;137:3144–7.
Cunningham MJ, Clifton DK, Steiner RA. Leptin’s actions on the reproductive axis: perspectives and mechanisms. Biol Reprod. 1999;60:216–22.
Mitchell M, et al. Adipokines: implications for female fertility and obesity. Reproduction. 2005;130:583–97.
Loffler S, et al. Evidence of leptin expression in normal and polycystic human ovaries. Mol Hum Reprod. 2001;7:1143–9.
Duggal PS, et al. The in vivo and in vitro effects of exogenous leptin on ovulation in the rat. Endocrinology. 2000;141:1971–6.
Cioffi JA, et al. Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nat Med. 1996;2:585–9.
Lin XH, et al. Leptin down-regulates gamma-ENaC expression: a novel mechanism involved in low endometrial receptivity. Fertil Steril. 2015;103:228–35. e3
Arita Y, et al. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun. 1999;257:79–83.
Weyer C, et al. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab. 2001;86:1930–5.
Vilarrasa N, et al. Distribution and determinants of adiponectin, resistin and ghrelin in a randomly selected healthy population. Clin Endocrinol (Oxf). 2005;63:329–35.
Ardawi MS, Rouzi AA. Plasma adiponectin and insulin resistance in women with polycystic ovary syndrome. Fertil Steril. 2005;83:1708–16.
Aroda V, et al. Circulating and cellular adiponectin in polycystic ovary syndrome: relationship to glucose tolerance and insulin action. Fertil Steril. 2008;89:1200–8.
Lagaly DV, et al. Role of adiponectin in regulating ovarian theca and granulosa cell function. Mol Cell Endocrinol. 2008;284:38–45.
Hamed HO. Role of adiponectin and its receptor in prediction of reproductive outcome of metformin treatment in patients with polycystic ovarian syndrome. J Obstet Gynaecol Res. 2013;39:1596–603.
Lebovitz HE. Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes. 2001;109:S135–48.
Stepto NK, et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum Reprod. 2013;28:777–84.
Cussons AJ, et al. Cardiometabolic risk in polycystic ovary syndrome: a comparison of different approaches to defining the metabolic syndrome. Hum Reprod. 2008;23:2352–8.
Geffner ME, et al. Persistence of insulin resistance in polycystic ovarian disease after inhibition of ovarian steroid secretion. Fertil Steril. 1986;45:327–33.
Diamanti-Kandarakis E, et al. Insulin sensitivity and antiandrogenic therapy in women with polycystic ovary syndrome. Metabolism. 1995;44:525–31.
Barbieri RL, Makris A, Ryan KJ. Insulin stimulates androgen accumulation in incubations of human ovarian stroma and theca. Obstet Gynecol. 1984;64(3 Suppl):73S–80S.
Hernandez ER, et al. Insulin as a regulator of androgen biosynthesis by cultured rat ovarian cells: cellular mechanism(s) underlying physiological and pharmacological hormonal actions. Endocrinology. 1988;122:2034–43.
Adashi EY, Hsueh AJ, Yen SS. Insulin enhancement of luteinizing hormone and follicle-stimulating hormone release by cultured pituitary cells. Endocrinology. 1981;108:1441–9.
Teede HJ, Stuckey BG. Polycystic ovary syndrome and abnormal glucose tolerance. Med J Aust. 2007;187:324–5.
Nestler JE, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83–9.
Lee PD, Conover CA, Powell DR. Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exp Biol Med. 1993;204:4–29.
Ibanez L, et al. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J Clin Endocrinol Metab. 1997;82:2283–8.
De Leo V, et al. Effect of metformin on insulin-like growth factor (IGF) I and IGF-binding protein I in polycystic ovary syndrome. J Clin Endocrinol Metab. 2000;85:1598–600.
Franks S, et al. Insulin action in the normal and polycystic ovary. Endocrinol Metab Clin North Am. 1999;28:361–78.
Diamanti-Kandarakis E, et al. Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome. Eur J Endocrinol. 2010;162:193–212.
Nestler JE, Jakubowicz DJ. Decreases in ovarian cytochrome P450c17 alpha activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med. 1996;335:617–23.
Xu B, et al. Regulation of endometrial receptivity by the highly expressed HOXA9, HOXA11 and HOXD10 HOX-class homeobox genes. Hum Reprod. 2014;29:781–90.
Quezada S, et al. Evaluation of steroid receptors, coregulators, and molecules associated with uterine receptivity in secretory endometria from untreated women with polycystic ovary syndrome. Fertil Steril. 2006;85:1017–26.
Apparao KB, et al. Elevated endometrial androgen receptor expression in women with polycystic ovarian syndrome. Biol Reprod. 2002;66:297–304.
Giudice LC. Endometrium in PCOS: implantation and predisposition to endocrine CA. Best Pract Res Clin Endocrinol Metab. 2006;20:235–44.
Balen AH, et al. Miscarriage rates following in-vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod. 1993;8:959–64.
Sagle M, et al. Recurrent early miscarriage and polycystic ovaries. BMJ. 1988;297:1027–8.
Rees DA, Jenkins-Jones S, Morgan CL. Contemporary reproductive outcomes for patients with polycystic ovary syndrome: a retrospective observational study. J Clin Endocrinol Metab. 2016;101:1664–72.
West S, et al. Irregular menstruation and hyperandrogenaemia in adolescence are associated with polycystic ovary syndrome and infertility in later life: northern Finland birth cohort 1986 study. Hum Reprod. 2014;29:2339–51.
Palomba S, et al. Pregnancy complications in women with polycystic ovary syndrome. Hum Reprod Update. 2015;21:575–92.
Cakmak H, Taylor HS. Implantation failure: molecular mechanisms and clinical treatment. Hum Reprod Update. 2011;17:242–53.
Piltonen TT. Polycystic ovary syndrome: endometrial markers. Best Pract Res Clin Obstet Gynaecol. 2016;37:66–79.
Gonzalez D, et al. Loss of WT1 expression in the endometrium of infertile PCOS patients: a hyperandrogenic effect? J Clin Endocrinol Metab. 2012;97:957–66.
Baracat MC, et al. Systematic review of cell adhesion molecules and estrogen receptor expression in the endometrium of patients with polycystic ovary syndrome. Int J Gynaecol Obstet. 2015;129:1–4.
Lopes IM, et al. Endometrium in women with polycystic ovary syndrome during the window of implantation. Rev Assoc Med Bras. 2011;57:702–9.
Ludwig M, et al. Oocyte quality and treatment outcome in intracytoplasmic sperm injection cycles of polycystic ovarian syndrome patients. Hum Reprod. 1999;14:354–8.
Boomsma CM, Fauser BC, Macklon NS. Pregnancy complications in women with polycystic ovary syndrome. Semin Reprod Med. 2008;26:72–84.
Heijnen EM, et al. A meta-analysis of outcomes of conventional IVF in women with polycystic ovary syndrome. Hum Reprod Update. 2006;12:13–21.
Sahu B, et al. Comparison of oocyte quality and intracytoplasmic sperm injection outcome in women with isolated polycystic ovaries or polycystic ovarian syndrome. Arch Gynecol Obstet. 2008;277:239–44.
Mulders AG, et al. IVF outcome in anovulatory infertility (WHO group 2)–including polycystic ovary syndrome–following previous unsuccessful ovulation induction. Reprod Biomed Online. 2003;7:50–8.
Sengoku K, et al. The chromosomal normality of unfertilized oocytes from patients with polycystic ovarian syndrome. Hum Reprod. 1997;12:474–7.
Kenigsberg S, et al. Gene expression microarray profiles of cumulus cells in lean and overweight-obese polycystic ovary syndrome patients. Mol Hum Reprod. 2009;15:89–103.
Kwon H, et al. mRNA expression pattern of insulin-like growth factor components of granulosa cells and cumulus cells in women with and without polycystic ovary syndrome according to oocyte maturity. Fertil Steril. 2010;94:2417–20.
Dumesic DA, Abbott DH. Implications of polycystic ovary syndrome on oocyte development. Semin Reprod Med. 2008;26:53–61.
Dumesic DA, Abbott DH, Padmanabhan V. Polycystic ovary syndrome and its developmental origins. Rev Endocr Metab Disord. 2007;8:127–41.
Wood JR, et al. Molecular abnormalities in oocytes from women with polycystic ovary syndrome revealed by microarray analysis. J Clin Endocrinol Metab. 2007;92:705–13.
Franks S, Roberts R, Hardy K. Gonadotrophin regimens and oocyte quality in women with polycystic ovaries. Reprod Biomed Online. 2003;6:181–4.
Huang Y, et al. Impaired oocyte quality induced by dehydroepiandrosterone is partially rescued by metformin treatment. PLoS One. 2015;10:e0122370.
Kdous M, et al. Oocyte and embryo quality and outcome of ICSI cycles in patients with polycystic ovary syndrome (PCOS) versus normo-ovulatory. J Gynecol Obstet Biol Reprod (Paris). 2009;38:133–43.
Sermondade N, et al. Impact of polycystic ovary syndrome on oocyte and embryo quality. Gynecol Obstet Fertil. 2013;41:27–30.
Sigala J, et al. Is polycystic ovarian morphology related to a poor oocyte quality after controlled ovarian hyperstimulation for intracytoplasmic sperm injection? Results from a prospective, comparative study. Fertil Steril. 2015;103:112–8.
Bouillon R, et al. Vitamin D metabolism and action. Osteoporos Int. 1998;8:S13–9.
Wagner CL, et al. Vitamin D and its role during pregnancy in attaining optimal health of mother and fetus. Nutrients. 2012;4:208–30.
Thomson RL, Spedding S, Buckley JD. Vitamin D in the aetiology and management of polycystic ovary syndrome. Clin Endocrinol (Oxf). 2012;77:343–50.
Forrest KY, Stuhldreher WL. Prevalence and correlates of vitamin D deficiency in US adults. Nutr Res. 2011;31:48–54.
de Groot PC, et al. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:495–500.
Khanna R, Wu X, Shen B. Low levels of vitamin D are common in patients with ileal pouches irrespective of pouch inflammation. J Crohns Colitis. 2013;7:525–33.
Gallea M, et al. Insulin and body weight but not hyperandrogenism seem involved in seasonal serum 25-OH-vitamin D3 levels in subjects affected by PCOS. Gynecol Endocrinol. 2014;30:739–45.
Wehr E, et al. Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol. 2009;161:575–82.
Hahn S, et al. Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome. Exp Clin Endocrinol Diabetes. 2006;114:577–83.
Ngo DT, et al. Determinants of insulin responsiveness in young women: impact of polycystic ovarian syndrome, nitric oxide, and vitamin D. Nitric Oxide. 2011;25:326–30.
He C, et al. Serum vitamin D levels and polycystic ovary syndrome: a systematic review and meta-analysis. Nutrients. 2015;7:4555–77.
Zadeh-Vakili A, et al. Genetic polymorphism of vitamin D receptor gene affects the phenotype of PCOS. Gene. 2013;515:193–6.
Rudick B, et al. Characterizing the influence of vitamin D levels on IVF outcomes. Hum Reprod. 2012;27:3321–7.
Ozkan S, et al. Replete vitamin D stores predict reproductive success following in vitro fertilization. Fertil Steril. 2010;94:1314–9.
Rudick BJ, et al. Influence of vitamin D levels on in vitro fertilization outcomes in donor-recipient cycles. Fertil Steril. 2014;101:447–52.
Estes SJ, et al. A proteomic analysis of IVF follicular fluid in women ≤32 years old. Fertil Steril. 2009;92:1569–78.
Irani M, Merhi Z. Role of vitamin D in ovarian physiology and its implication in reproduction: a systematic review. Fertil Steril. 2014;102:460–8. e3
Pal L, et al. Vitamin D status relates to reproductive outcome in women with polycystic ovary syndrome: secondary analysis of a multicenter randomized controlled trial. J Clin Endocrinol Metab. 2016;101:3027–35.
Asadi M, et al. Vitamin D improves endometrial thickness in PCOS women who need intrauterine insemination: a randomized double-blind placebo-controlled trial. Arch Gynecol Obstet. 2014;289:865–70.
Selimoglu H, et al. The effect of vitamin D replacement therapy on insulin resistance and androgen levels in women with polycystic ovary syndrome. J Endocrinol Invest. 2010;33:234–8.
Ardabili HR, Gargari BP, Farzadi L. Vitamin D supplementation has no effect on insulin resistance assessment in women with polycystic ovary syndrome and vitamin D deficiency. Nutr Res. 2012;32:195–201.
Practice Committee of the American Society for Reproductive Medicine. Diagnostic evaluation of the infertile female: a committee opinion. Fertil Steril. 2015;103:e44–50.
Singh KB, Patel YC, Wortsman J. Coexistence of polycystic ovary syndrome and pelvic endometriosis. Obstet Gynecol. 1989;74:650–2.
Wise LA, et al. Polycystic ovary syndrome and risk of uterine leiomyomata. Fertil Steril. 2007;87:1108–15.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2018 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Shavit, T., Tulandi, T. (2018). Infertility and Subfertility Cofactors in Women with PCOS. In: Palomba, S. (eds) Infertility in Women with Polycystic Ovary Syndrome. Springer, Cham. https://doi.org/10.1007/978-3-319-45534-1_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-45534-1_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-45533-4
Online ISBN: 978-3-319-45534-1
eBook Packages: MedicineMedicine (R0)