The management of patients with polycystic ovary syndrome

Nature Reviews Endocrinology

Volumn 10, Issue 10, 2014, Pages 624-636

  Jayasena, Channa N ^a   Franks, Stephen ^b  

^a Institute of Reproductive and Developmental Biology   (United Kingdom)

^b HAMMERSMITH HOSPITAL   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ANDROGEN; ANDROSTENEDIONE; ANTIANDROGEN; ANTIESTROGEN; AROMATASE INHIBITOR; CLOMIFENE CITRATE; CYPROTERONE ACETATE; CYPROTERONE ACETATE PLUS ETHINYLESTRADIOL; EFLORNITHINE; FINASTERIDE; FLUTAMIDE; FOLLITROPIN; GESTAGEN; GONADOTROPIN RECEPTOR; HUMAN MENOPAUSAL GONADOTROPIN; LUTEINIZING HORMONE; METFORMIN; ORAL CONTRACEPTIVE AGENT; RECOMBINANT FOLLITROPIN; SPIRONOLACTONE; TESTOSTERONE;

AMENORRHEA; ANDROGEN BLOOD LEVEL; ANDROSTENEDIONE BLOOD LEVEL; ANOVULATION; ANTIANDROGEN THERAPY; CARDIOMETABOLIC RISK; CARDIOVASCULAR DISEASE; CHROMOSOME 2P; DIABETES MELLITUS; DIATHERMY; DIET; DYSLIPIDEMIA; ENVIRONMENTAL FACTOR; FAMILY HISTORY; FEMALE INFERTILITY; FERTILIZATION IN VITRO; FOLLITROPIN RELEASE; GENERAL PRACTITIONER; GONADOTROPIN RELEASE; HIRSUTISM; HUMAN; HYPERANDROGENISM; HYPERPROLACTINEMIA; HYPOTHALAMIC AMENORRHEA; HYPOTHYROIDISM; IMPAIRED GLUCOSE TOLERANCE; INSULIN RESISTANCE; LAPAROSCOPY; LIFESTYLE MODIFICATION; LIQUID CHROMATOGRAPHY; LOW LEVEL LASER THERAPY; LUTEINIZING HORMONE RELEASE; MASS SPECTROMETRY; MENSTRUAL IRREGULARITY; META ANALYSIS (TOPIC); NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; OLIGOMENORRHEA; OVARY POLYCYSTIC DISEASE; OVULATION; PATHOPHYSIOLOGY; PREMATURE OVARIAN FAILURE; PRIORITY JOURNAL; RADIOIMMUNOASSAY; REVIEW; SYSTEMATIC REVIEW (TOPIC); TESTOSTERONE BLOOD LEVEL; THYROID FUNCTION TEST; ANIMAL; BLOOD; DIABETES MELLITUS, TYPE 2; DISEASE MANAGEMENT; FEMALE; PHYSIOLOGY; POLYCYSTIC OVARY SYNDROME; RISK REDUCTION;

ANDROGEN ANTAGONISTS; ANDROGENS; ANIMALS; DIABETES MELLITUS, TYPE 2; DISEASE MANAGEMENT; FEMALE; HIRSUTISM; HUMANS; INSULIN RESISTANCE; POLYCYSTIC OVARY SYNDROME; RISK REDUCTION BEHAVIOR;

EID: 84926197752     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2014.102     Document Type: Review

References (173)

1. Azziz, R. et al. Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: A multicenter, double blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 86, 1626-1632 (2001).
2. Fauser, B. C. et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil. Steril. 97, 28-38.e25 (2012).
3. March, W. A. et al. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum. Reprod. 25, 544-551 (2010).
4. Stein, I. F. Sr. The Stein-Leventhal syndrome. West. J. Surg. Obstet. Gynecol. 63, 319-323 (1955).
5. Stein, I. F. Sr. Duration of fertility following ovarian wedge resection-Stein-Leventhal syndrome. West. J. Surg. Obstet. Gynecol. 72, 237-242 (1964).
6. Franks, S. The ubiquitous polycystic ovary. J. Endocrinol. 129, 317-319 (1991).
7. Wajchenberg, B. L. et al. Determination of the source(s) of androgen overproduction in hirsutism associated with polycystic ovary syndrome by simultaneous adrenal and ovarian venous catheterization. Comparison with the dexamethasone suppression test. J. Clin. Endocrinol. Metab. 63, 1204-1210 (1986).
8. Franks, S., Gilling-Smith, C., Watson, H. & Willis, D. Insulin action in the normal and polycystic ovary. Endocrinol. Metab. Clin. North Am. 28, 361-378 (1999).
9. Moran, C., Reyna, R., Boots, L. S. & Azziz, R. Adrenocortical hyperresponsiveness to corticotropin in polycystic ovary syndrome patients with adrenal androgen excess. Fertil. Steril. 81, 126-131 (2004).
10. Kumar, A., Woods, K. S., Bartolucci, A. A. & Azziz, R. Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS). Clin. Endocrinol. (Oxf.) 62, 644-649 (2005).
11. Wickenheisser, J. K., Nelson-DeGrave, V. L. & McAllister, J. M. Human ovarian theca cells in culture. Trends Endocrinol. Metab. 17, 65-71 (2006).
12. Pardridge, W. M. Transport of protein-bound hormones into tissues in vivo. Endocr. Rev. 2, 103-123 (1981).
13. Eagleson, C. A. et al. Polycystic ovarian syndrome: evidence that flutamide restores sensitivity of the gonadotropin-releasing hormone pulse generator to inhibition by estradiol and progesterone. J. Clin. Endocrinol. Metab. 85, 4047-4052 (2000).
14. Blank, S. K., McCartney, C. R. & Marshall, J. C. The origins and sequelae of abnormal neuroendocrine function in polycystic ovary syndrome. Hum. Reprod. Update 12, 351-361 (2006).
15. Rebar, R. et al. Characterization of the inappropriate gonadotropin secretion in polycystic ovary syndrome. J. Clin. Invest. 57, 1320-1329 (1976).
16. Baird, D. T. et al. Pituitary-ovarian relationships in polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 45, 798-801 (1977).
17. Franks, S., Stark, J. & Hardy, K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum. Reprod. Update 14, 367-378 (2008).
18. Chavez-Ross, A., Franks, S., Mason, H. D., Hardy, K. & Stark, J. Modelling the control of ovulation and polycystic ovary syndrome. J. Math. Biol. 36, 95-118 (1997).
19. Diamanti-Kandarakis, E. & Dunaif, A. Insulin resistance and the polycystic ovary syndrome revisited: An update on mechanisms and implications. Endocr. Rev. 33, 981-1030 (2012).
20. Manneras-Holm, L. et al. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J. Clin. Endocrinol. Metab. 96, E304-E311 (2011).
21. Stepto, N. K. et al. Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic-hyperinsulaemic clamp. Hum. Reprod. 28, 777-784 (2013).
22. Barber, T. M. & Franks, S. Adipocyte biology in polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 68-76 (2013).
23. Pasquali, R. et al. Body fat distribution has weight-independent effects on clinical, hormonal, and metabolic features of women with polycystic ovary syndrome. Metabolism 43, 706-713 (1994).
24. Kirchengast, S. & Huber, J. Body composition characteristics and body fat distribution in lean women with polycystic ovary syndrome. Hum. Reprod. 16, 1255-1260 (2001).
25. Abbott, D. H., Dumesic, D. A. & Franks, S. Developmental origin of polycystic ovary syndrome-a hypothesis. J. Endocrinol. 174, 1-5 (2002).
26. Padmanabhan, V., Veiga-Lopez, A., Abbott, D. H., Recabarren, S. E. & Herkimer, C. Developmental programming: impact of prenatal testosterone excess and postnatal weight gain on insulin sensitivity index and transfer of traits to offspring of overweight females. Endocrinology 151, 595-605 (2010).
27. Abbott, D. H. et al. Nonhuman primate models of polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 21-28 (2013).
28. Barbieri, R. L. et al. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J. Clin. Endocrinol. Metab. 62, 904-910 (1986).
29. Plymate, S. R., Matej, L. A., Jones, R. E. & Friedl, K. E. Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J. Clin. Endocrinol. Metab. 67, 460-464 (1988).
30. Legro, R. S., Driscoll, D., Strauss, J. F. 3rd, Fox, J. & Dunaif, A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc. Natl Acad. Sci. USA 95, 14956-14960 (1998).
31. Franks, S. et al. Ovarian morphology is a marker of heritable biochemical traits in sisters with polycystic ovaries. J. Clin. Endocrinol. Metab. 93, 3396-3402 (2008).
32. Vink, J. M., Sadrzadeh, S., Lambalk, C. B. & Boomsma, D. I. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J. Clin. Endocrinol. Metab. 91, 2100-2104 (2006).
33. Kosova, G & Urbanek, M. Genetics of the polycystic ovary syndrome. Mol. Cell. Endocrinol. 373, 29-38 (2013).
34. Mutharasan, P. et al. Evidence for chromosome 2p16.3 polycystic ovary syndrome susceptibility locus in affected women of European ancestry. J. Clin. Endocrinol. Metab. 98, E185-E190 (2013).
35. Chen, Z. J. et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat. Genet. 43, 55-59 (2011).
36. Shi, Y. et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat. Genet. 44, 1020-1025 (2012).
37. Welt, C. K. et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J. Clin. Endocrinol. Metab. 97, E1342-E1347 (2012).
38. Louwers, Y. V., Stolk, L., Uitterlinden, A. G. & Laven, J. S. Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 98, E2006-E2012 (2013).
39. Diamanti-Kandarakis, E., Kandarakis, H. & Legro, R. S. The role of genes and environment in the etiology of PCOS. Endocrine 30, 19-26 (2006).
40. Kiddy, D. S. et al. Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: An analysis of 263 consecutive cases. Clin. Endocrinol. (Oxf.) 32, 213-220 (1990).
41. Deligeoroglou, E. et al. Mediators of chronic inflammation in polycystic ovarian syndrome. Gynecol. Endocrinol. 28, 974-978 (2012).
42. Diamanti-Kandarakis, E. Role of obesity and adiposity in polycystic ovary syndrome. Int. J. Obes. (Lond.) 31 (Suppl. 2), S8-S13 (2007).
43. Livadas, S. & Diamanti-Kandarakis, E. Polycystic ovary syndrome: definitions, phenotypes and diagnostic approach. Front. Horm. Res. 40, 1-21 (2013).
44. Zawadzki, J. K. & Dunaif, A. in Polycystic Ovary Syndrome (eds Dunaif, A., Givens, J. R., Haseltine, F. P. & Merriam, G. R.) 377-384 (Blackwell 1992).
45. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum. Reprod. 19, 41-47 (2004).
46. Azziz, R. et al. Positions statement: criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An Androgen Excess Society guideline. J. Clin. Endocrinol. Metab. 91, 4237-4245 (2006).
47. Dewailly, D. et al. Definition and significance of polycystic ovarian morphology: A task force report from the Androgen Excess and Polycystic Ovary Syndrome Society. Hum. Reprod. Update 20, 334-352 (2014).
48. Goverde, A. J. et al. Indicators for metabolic disturbances in anovulatory women with polycystic ovary syndrome diagnosed according to the Rotterdam consensus criteria. Hum. Reprod. 24, 710-717 (2009).
49. Dunaif, A. & Fauser, B. C. Renaming PCOS-a two-state solution. J. Clin. Endocrinol. Metab. 98, 4325-4328 (2013).
50. Moran, L. & Teede, H. Metabolic features of the reproductive phenotypes of polycystic ovary syndrome. Hum. Reprod. Update 15, 477-488 (2009).
51. Moghetti, P. et al. Divergences in insulin resistance between the different phenotypes of the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 98, E628-E637 (2013).
52. Teede, H., Gibson-Helm, M., Norman, R. J. & Boyle, J. Polycystic ovary syndrome: perceptions and attitudes of women and primary health care physicians on features of PCOS and renaming the syndrome. J. Clin. Endocrinol. Metab. 99, E107-E111 (2014).
53. Legro, R. S. et al. Diagnosis and treatment of polycystic ovary syndrome: An Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 98, 4565-4592 (2013).
54. Ladenson, P. W. et al. American Thyroid Association guidelines for detection of thyroid dysfunction. Arch. Intern. Med. 160, 1573-1575 (2000).
55. Franks, S. Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J. Clin. Endocrinol. Metab. 91, 786-789 (2006).
56. Rosner, W., Auchus, R. J., Azziz, R., Sluss, P. M. & Raff, H. Position statement: Utility, limitations, and pitfalls in measuring testosterone: An Endocrine Society position statement. J. Clin. Endocrinol. Metab. 92, 405-413 (2007).
57. Legro, R. S. et al. Total testosterone assays in women with polycystic ovary syndrome: precision and correlation with hirsutism. J. Clin. Endocrinol. Metab. 95, 5305-5313 (2010).
58. Miller, K. K. et al. Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods. J. Clin. Endocrinol. Metab. 89, 525-533 (2004).
59. Vermeulen, A., Verdonck, L. & Kaufman, J. M. A critical evaluation of simple methods for the estimation of free testosterone in serum. J. Clin. Endocrinol. Metab. 84, 3666-3672 (1999).
60. Hahn, S. et al. Diagnostic value of calculated testosterone indices in the assessment of polycystic ovary syndrome. Clin. Chem. Lab. Med. 45, 202-207 (2007).
61. Broekmans, F. J. et al. Anti-Müllerian hormone and ovarian dysfunction. Trends Endocrinol. Metab. 19, 340-347 (2008).
62. Klein, D. A. & Poth, M. A. Amenorrhea: An approach to diagnosis and management. Am. Fam. Physician 87, 781-788 (2013).
63. Lowenstein, E. J. Diagnosis and management of the dermatologic manifestations of the polycystic ovary syndrome. Dermatol. Ther. 19, 210-223 (2006).
64. Trueb, R. M. Causes and management of hypertrichosis. Am. J. Clin. Dermatol. 3, 617-627 (2002).
65. Sanchez, L. A., Perez, M. & Azziz, R. Laser hair reduction in the hirsute patient: A critical assessment. Hum. Reprod. Update 8, 169-181 (2002).
66. Moghetti, P. & Toscano, V. Treatment of hirsutism and acne in hyperandrogenism. Best Pract. Res. Clin. Endocrinol. Metab. 20, 221-234 (2006).
67. Richards, R. N. Electrolysis for the treatment of hypertrichosis and hirsutism. Skin Therapy Lett. 4, 3-4 (1999).
68. Balfour, J. A. & McClellan, K. Topical eflornithine. Am. J. Clin. Dermatol. 2, 197-201 (2001).
69. Givens, J. R., Andersen, R. N., Wiser, W. L. & Fish, S. A. Dynamics of suppression and recovery of plasma FSH, LH, androstenedione and testosterone in polycystic ovarian disease using an oral contraceptive. J. Clin. Endocrinol. Metab. 38, 727-735 (1974).
70. Wild, R. A., Umstot, E. S., Andersen, R. N. & Givens, J. R. Adrenal function in hirsutism. II. Effect of an oral contraceptive. J. Clin. Endocrinol. Metab. 54, 676-681 (1982).
71. Eil, C. & Edelson, S. K. The use of human skin fibroblasts to obtain potency estimates of drug binding to androgen receptors. J. Clin. Endocrinol. Metab. 59, 51-55 (1984).
72. Neumann, F. et al. Aspects of androgen-dependent events as studied by antiandrogens. Recent Prog. Horm. Res. 26, 337-410 (1970).
73. MHRA. Cyproterone acetate with ethinylestradiol (co-cyprindiol): balance of benefits and risks remains positive-updated prescribing advice provided [online], http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON287002 (2013).
74. Wu, O. et al. Screening for thrombophilia in high-risk situations: Systematic review and cost-effectiveness analysis. The Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) study. Health Technol. Assess. 10, 1-110 (2006).
75. Centers for Disease Control and Prevention (CDC). US medical eligibility criteria for contraceptive use, 2010. MMWR Recomm. Rep. 59, 1-86 (2010).
76. Okoroh, E. M., Hooper, W. C., Atrash, H. K., Yusuf, H. R. & Boulet, S. L. Is polycystic ovary syndrome another risk factor for venous thromboembolism' United States, 2003-2008. Am. J. Obstet. Gynecol. 207, 377.e1-377.e8 (2012).
77. Lidegaard, O., Lokkegaard, E., Jensen, A., Skovlund, C. W. & Keiding, N. Thrombotic stroke and myocardial infarction with hormonal contraception. N. Engl. J. Med. 366, 2257-2266 (2012).
78. Shapiro, G. & Evron, S. A novel use of spironolactone: treatment of hirsutism. J. Clin. Endocrinol. Metab. 51, 429-432 (1980).
79. Cumming, D. C., Yang, J. C., Rebar, R. W. & Yen, S. S. Treatment of hirsutism with spironolactone. JAMA 247, 1295-1298 (1982).
80. Menard, R. H., Guenthner, T. M., Kon, H. & Gillette, J. R. Studies on the destruction of adrenal and testicular cytochrome P450 by spironolactone. Requirement for the 7'-thio group and evidence for the loss of the heme and apoproteins of cytochrome P450. J. Biol. Chem. 254, 1726-1733 (1979).
81. Corvol, P., Michaud, A., Menard, J., Freifeld, M. & Mahoudeau, J. Antiandrogenic effect of spirolactones: mechanism of action. Endocrinology 97, 52-58 (1975).
82. Siegberg, R., Ylostalo, P., Laatikainen, T., Pelkonen, R. & Stenman, U. H. Endocrine and clinical effects of spironolactone in female hyperandrogenism. Arch. Gynecol. 240, 67-73 (1987).
83. van Vloten, W. A., van Haselen, C. W., van Zuuren, E. J., Gerlinger, C. & Heithecker, R. The effect of 2 combined oral contraceptives containing either drospirenone or cyproterone acetate on acne and seborrhea. Cutis 69, 2-15 (2002).
84. Bhattacharya, S. M. & Jha, A. Comparative study of the therapeutic effects of oral contraceptive pills containing desogestrel, cyproterone acetate, and drospirenone in patients with polycystic ovary syndrome. Fertil. Steril. 98, 1053-1059 (2012).
85. Erenus, M., Yucelten, D., Durmusoglu, F. & Gurbuz, O. Comparison of finasteride versus spironolactone in the treatment of idiopathic hirsutism. Fertil. Steril. 68, 1000-1003 (1997).
86. Falsetti, L., Gambera, A., Legrenzi, L., Iacobello, C. & Bugari, G. Comparison of finasteride versus flutamide in the treatment of hirsutism. Eur. J. Endocrinol. 141, 361-367 (1999).
87. Petrone, A. et al. Usefulness of a 12-month treatment with finasteride in idiophathic and polycystic ovary syndrome-associated hirsutism. Clin. Exp. Obstet. Gynecol. 26, 213-216 (1999).
88. Tolino, A. et al. Finasteride in the treatment of hirsutism: new therapeutic perspectives. Fertil. Steril. 66, 61-65 (1996).
89. Moghetti, P. et al. Comparison of spironolactone, flutamide, and finasteride efficacy in the treatment of hirsutism: A randomized, double blind, placebo-controlled trial. J. Clin. Endocrinol. Metab. 85, 89-94 (2000).
90. Solomon, C. G. et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 286, 2421-2426 (2001).
91. Moran, L. J., Pasquali, R., Teede, H. J., Hoeger, K. M. & Norman, R. J. Treatment of obesity in polycystic ovary syndrome: A position statement of the Androgen Excess and Polycystic Ovary Syndrome Society. Fertil. Steril. 92, 1966-1982 (2009).
92. Diamanti-Kandarakis, E. PCOS in adolescents. Best Pract. Res. Clin. Obstet. Gynaecol. 24, 173-183 (2010).
93. Ornstein, R. M., Copperman, N. M. & Jacobson, M. S. Effect of weight loss on menstrual function in adolescents with polycystic ovary syndrome. J. Pediatr. Adolesc. Gynecol. 24, 161-165 (2011).
94. Lass, N., Kleber, M., Winkel, K., Wunsch, R. & Reinehr, T. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic syndrome, and intima-media thickness in obese adolescent girls. J. Clin. Endocrinol. Metab. 96, 3533-3540 (2011).
95. Mansfield, R., Galea, R., Brincat, M., Hole, D. & Mason, H. Metformin has direct effects on human ovarian steroidogenesis. Fertil. Steril. 79, 956-962 (2003).
96. Costello, M., Shrestha, B., Eden, J., Sjoblom, P. & Johnson, N. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD005552 http://dx.doi.org/10.1002/14651858.CD005552.pub2.
97. Moghetti, P. et al. Metformin effects on clinical features, endocrine and metabolic profiles, and insulin sensitivity in polycystic ovary syndrome: A randomized, double-blind, placebo-controlled 6month trial, followed by open, long-term clinical evaluation. J. Clin. Endocrinol. Metab. 85, 139-146 (2000).
98. Gorry, A., White, D. M. & Franks, S. Infertility in polycystic ovary syndrome: focus on low-dose gonadotropin treatment. Endocrine 30, 27-33 (2006).
99. Sirmans, S. M. & Pate, K. A. Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clin. Epidemiol. 6, 1-13 (2013).
100. Panidis, D., Tziomalos, K., Papadakis, E. & Katsikis, I. Infertility treatment in polycystic ovary syndrome: lifestyle interventions, medications and surgery. Front. Horm. Res. 40, 128-141 (2013).
101. Kiddy, D. S. et al. Improvement in endocrine and ovarian function during dietary treatment of obese women with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 36, 105-111 (1992).
102. Moran, L. J., Hutchison, S. K., Norman, R. J. & Teede, H. J. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews, Issue 7. Art. No.: CD007506. http://dx.doi.org/10.1002/14651858.CD007506.pub3.
103. Adashi, E. Y. Clomiphene citrate: mechanism(s) and site(s) of action-a hypothesis revisited. Fertil. Steril. 42, 331-344 (1984).
104. Thessaloniki ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Consensus on infertility treatment related to polycystic ovary syndrome. Hum. Reprod. 23, 462-477 (2008).
105. Hull, M. in Infertility Ch. 3 (ed. Templeton, A. A.) 33-62 (Springer-Verlag, 1992).
106. Humaidan, P., Quartarolo, J. & Papanikolaou, E. G. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil. Steril. 94, 389-400 (2010).
107. Tang, T. et al. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum. Reprod. 21, 80-89 (2006).
108. Lord, J. M., Flight, I. H. & Norman, R. J. Metformin in polycystic ovary syndrome: Systematic review and meta-analysis. BMJ 327, 951-953 (2003).
109. Moll, E., Bossuyt, P. M., Korevaar, J. C., Lambalk, C. B. & van der Veen, F. Effect of clomifene citrate plus metformin and clomifene citrate plus placebo on induction of ovulation in women with newly diagnosed polycystic ovary syndrome: randomised double blind clinical trial. BMJ 332, 1485 (2006).
110. Legro, R. S. et al. Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome. N. Engl. J. Med. 356, 551-566 (2007).
111. Tang, T., Lord, J. M., Norman, R. J., Yasmin, E. & Balen, A. H. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, Dchiroinositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database of Systematic Reviews, Issue 5. Art. No.: CD003053. http://dx.doi.org/10.1002/14651858.CD003053.pub5.
112. Johnson, N. Metformin is a reasonable first-line treatment option for non-obese women with infertility related to anovulatory polycystic ovary syndrome-a meta-analysis of randomised trials. Aust. NZ J. Obstet. Gynaecol. 51, 125-129 (2011).
113. Misso, M. L. et al. Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. Update 19, 2-11 (2013).
114. Saltiel, A. R. & Olefsky, J. M. Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45, 1661-1669 (1996).
115. Pavone, M. E. & Bulun, S. E. Clinical review: the use of aromatase inhibitors for ovulation induction and superovulation. J. Clin. Endocrinol. Metab. 98, 1838-1844 (2013).
116. Polyzos, N. P. et al. Aromatase inhibitors for infertility in polycystic ovary syndrome. The beginning or the end of a new era' Fertil. Steril. 89, 278-280 (2008).
117. Badawy, A., Shokeir, T., Allam, A. F. & Abdelhady, H. Pregnancy outcome after ovulation induction with aromatase inhibitors or clomiphene citrate in unexplained infertility. Acta Obstet. Gynecol. Scand. 88, 187-191 (2009).
118. Roy, K. K. et al. A prospective randomized trial comparing the efficacy of letrozole and clomiphene citrate in induction of ovulation in polycystic ovarian syndrome. J. Hum. Reprod. Sci. 5, 20-25 (2012).
119. Kar, S. Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: A prospective randomized trial. J. Hum. Reprod. Sci. 5, 262-265 (2012).
120. Legro, R. S. et al. The Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial: rationale and design of a double-blind randomized trial of clomiphene citrate and letrozole for the treatment of infertility in women with polycystic ovary syndrome. Contemp. Clin. Trials 33, 470-481 (2012).
121. Wang, C. F. & Gemzell, C. The use of human gonadotropins for the induction of ovulation in women with polycystic ovarian disease. Fertil. Steril. 33, 479-486 (1980).
122. White, D. M. 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. 81, 3821-3824 (1996).
123. Farquhar, C., Brown, J. & Marjoribanks, J. Laparoscopic drilling by diathermy or laser for ovulation induction in anovulatory polycystic ovary syndrome. Cochrane Database of Systematic Reviews, Issue 6. Art. No.: CD001122. http://dx.doi.org/10.1002/14651858.CD001122.pub4.
124. Colditz, G. A., Willett, W. C., Rotnitzky, A. & Manson, J. E. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann. Intern. Med. 122, 481-486 (1995).
125. Koh-Banerjee, P. et al. Changes in body weight and body fat distribution as risk factors for clinical diabetes in US men. Am. J. Epidemiol. 159, 1150-1159 (2004).
126. Bogers, R. P. et al. Association of overweight with increased risk of coronary heart disease partly independent of blood pressure and cholesterol levels: A meta-analysis of 21 cohort studies including more than 300,000 persons. Arch. Intern. Med. 167, 1720-1728 (2007).
127. Rich-Edwards, J. W. et al. Physical activity, body mass index, and ovulatory disorder infertility. Epidemiology 13, 184-190 (2002).
128. Galani, C. & Schneider, H. Prevention and treatment of obesity with lifestyle interventions: review and meta-analysis. Int. J. Public. Health. 52, 348-359 (2007).
129. Escobar-Morreale, H. F., Botella-Carretero, J. I., Alvarez-Blasco, F., Sancho, J. & San Millan, J. L. The polycystic ovary syndrome associated with morbid obesity may resolve after weight loss induced by bariatric surgery. J. Clin. Endocrinol. Metab. 90, 6364-6369 (2005).
130. Eid, G. M. et al. Effective treatment of polycystic ovarian syndrome with RouxenY gastric bypass. Surg. Obes. Relat. Dis. 1, 77-80 (2005).
131. Kahal, H. et al. Glucagon-like peptide1 analogue, liraglutide, improves liver fibrosis markers in obese women with polycystic ovary syndrome and nonalcoholic fatty liver disease. Clin. Endocrinol. (Oxf.) http://dx.doi.org/10.1111/cen.12369 (2013).
132. Wilding, J. P. & Hardy, K. Glucagon-like peptide1 analogues for type 2 diabetes. BMJ 342, d410 (2011).
133. Gambineri, A. et al. Efficacy of octreotide-LAR in dieting women with abdominal obesity and polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 90, 3854-3862 (2005).
134. Rubio, M. A., Gargallo, M., Isabel Millan, A. & Moreno, B. Drugs in the treatment of obesity: Sibutramine, orlistat and rimonabant. Public Health Nutr. 10, 1200-1205 (2007).
135. Panidis, D. et al. The role of orlistat combined with lifestyle changes in the management of overweight and obese patients with polycystic ovary syndrome. Clin. Endocrinol. (Oxf.) 80, 432-438 (2014).
136. Dunaif, A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr. Rev. 18, 774-800 (1997).
137. Wild, S., Pierpoint, T., McKeigue, P. & Jacobs, H. Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: A retrospective cohort study. Clin. Endocrinol. (Oxf.) 52, 595-600 (2000).
138. Wild, R. A. et al. Assessment of cardiovascular risk and prevention of cardiovascular disease in women with the polycystic ovary syndrome: A consensus statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society. J. Clin. Endocrinol. Metab. 95, 2038-2049 (2010).
139. Ehrmann, D. A., Barnes, R. B., Rosenfield, R. L., Cavaghan, M. K. & Imperial, J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22, 141-146 (1999).
140. Legro, R. S., Kunselman, A. R., Dodson, W. C. & Dunaif, A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: A prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 84, 165-169 (1999).
141. Moran, L. J., Misso, M. L., Wild, R. A. & Norman, R. J. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. Update 16, 347-363 (2010).
142. Solomon, C. G. et al. Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 286, 2421-2426 (2001).
143. Boomsma, C. M. et al. A meta-analysis of pregnancy outcomes in women with polycystic ovary syndrome. Hum. Reprod. Update 12, 673-683 (2006).
144. Knowler, W. C. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 346, 393-403 (2002).
145. Diabetes Prevention Program Outcomes Study Research Group. Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: A report from the DPP Outcomes Study. Diabet. Med. 30, 46-55 (2013).
146. Moran, L. J., Hutchison, S. K., Norman, R. J. & Teede, H. J. Lifestyle changes in women with polycystic ovary syndrome. Cochrane Database of Systematic Reviews, Issue 7. Art. No.: CD007506. http://dx.doi.org.10.1002/14651858.CD007506.pub3.
147. Solomon, C. G. et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J. Clin. Endocrinol. Metab. 87, 2013-2017 (2002).
148. Meyer, M. L., Malek, A. M., Wild, R. A., Korytkowski, M. T. & Talbott, E. O. Carotid artery intima-media thickness in polycystic ovary syndrome: A systematic review and meta-analysis. Hum. Reprod. Update 18, 112-126 (2012).
149. Arad, Y. et al. Predictive value of electron beam computed tomography of the coronary arteries. 19-month follow-up of 1,173 asymptomatic subjects. Circulation 93, 1951-1953 (1996).
150. Talbott, E. O. et al. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 89, 5454-5461 (2004).
151. Shaw, L. J. et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health-National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation. J. Clin. Endocrinol. Metab. 93, 1276-1284 (2008).
152. Mani, H. et al. Diabetes and cardiovascular events in women with polycystic ovary syndrome: A 20-year retrospective cohort study. Clin. Endocrinol. (Oxf.) 78, 926-934 (2013).
153. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evidence report. National Institutes of Health. Obes. Res. 6 (Suppl. 2), 51S-209S (1998).
154. Wilson, P. W., D'Agostino, R. B., Sullivan, L., Parise, H. & Kannel, W. B. Overweight and obesity as determinants of cardiovascular risk: the Framingham experience. Arch. Intern. Med. 162, 1867-1872 (2002).
155. Wannamethee, S. G., Shaper, A. G. & Walker, M. Overweight and obesity and weight change in middle aged men: impact on cardiovascular disease and diabetes. J. Epidemiol. Community Health 59, 134-139 (2005).
156. Kassi, E. & Diamanti-Kandarakis, E. The effects of insulin sensitizers on the cardiovascular risk factors in women with polycystic ovary syndrome. J. Endocrinol. Invest. 31, 1124-1131 (2008).
157. Diamanti-Kandarakis, E. et al. Metformin administration improves endothelial function in women with polycystic ovary syndrome. Eur. J. Endocrinol. 152, 749-756 (2005).
158. Naka, K. K. et al. Effect of the insulin sensitizers metformin and pioglitazone on endothelial function in young women with polycystic ovary syndrome: A prospective randomized study. Fertil. Steril. 95, 203-209 (2011).
159. Jensterle, M. et al. Improvement of endothelial function with metformin and rosiglitazone treatment in women with polycystic ovary syndrome. Eur. J. Endocrinol. 159, 399-406 (2008).
160. Christakou, C. D. & Diamanti-Kandarakis, E. Role of androgen excess on metabolic aberrations and cardiovascular risk in women with polycystic ovary syndrome. Womens Health (Lond. Engl.) 4, 583-594 (2008).
161. Carmina, E., Chu, M. C., Longo, R. A., Rini, G. B. & Lobo, R. A. Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters. J. Clin. Endocrinol. Metab. 90, 2545-2549 (2005).
162. Valkenburg, O. et al. A more atherogenic serum lipoprotein profile is present in women with polycystic ovary syndrome: A case-control study. J. Clin. Endocrinol. Metab. 93, 470-476 (2008).
163. Diamanti-Kandarakis, E., Papavassiliou, A. G., Kandarakis, S. A. & Chrousos, G. P. Pathophysiology and types of dyslipidemia in PCOS. Trends Endocrinol. Metab. 18, 280-285 (2007).
164. Izquierdo, D., Foyouzi, N., Kwintkiewicz, J. & Duleba, A. J. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis. Fertil. Steril. 82 (Suppl. 3), 1193-1197 (2004).
165. Rzepczynska, I. J. et al. Role of isoprenylation in simvastatin-induced inhibition of ovarian theca-interstitial growth in the rat. Biol. Reprod. 81, 850-855 (2009).
166. Sokalska, A., Piotrowski, P. C., Rzepczynska, I. J., Cress, A. & Duleba, A. J. Statins inhibit growth of human theca-interstitial cells in PCOS and non-PCOS tissues independently of cholesterol availability. J. Clin. Endocrinol. Metab. 95, 5390-5394 (2010).
167. Ortega, I. et al. Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. Biol. Reprod. 86, 1-9 (2012).
168. Duleba, A. J., Banaszewska, B., Spaczynski, R. Z. & Pawelczyk, L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial. Fertil. Steril. 85, 996-1001 (2006).
169. Gao, L., Zhao, F. L. & Li, S. C. Statin is a reasonable treatment option for patients with polycystic ovary syndrome: A meta-analysis of randomized controlled trials. Exp. Clin. Endocrinol. Diabetes 120, 367-375 (2012).
170. Puurunen, J. et al. Statin therapy worsens insulin sensitivity in women with polycystic ovary syndrome (PCOS): A prospective, randomized, double-blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 98, 4798-4807 (2013).
171. Diamanti-Kandarakis, E., Mitrakou, A., Raptis, S., Tolis, G. & Duleba, A. J. The effect of a pure antiandrogen receptor blocker, flutamide, on the lipid profile in the polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 83, 2699-2705 (1998).
172. Franks, S. Polycystic ovary syndrome in adolescents. Int. J. Obes. (Lond.) 32, 1035-1041 (2008).
173. Franks, S., McCarthy, M. I. & Herdy, K. Development of polycystic ovary syndrome: involvement of genetic and environmental factors. Int. J. Androl. 29, 278-285 (2006).