Semin Reprod Med 2017; 35(04): 326-343
DOI: 10.1055/s-0037-1603729
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Pharmacologic Treatment of Polycystic Ovary Syndrome: Alternate and Future Paths

Luciana M. Martel Duguech
1   Department of Endocrinology and Metabolism, Hospital Ramos Mejia, Buenos Aires, Argentina
,
Richard S. Legro
2   Department of Obstetrics and Gynecology and Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania
› Author Affiliations
Further Information

Publication History

Publication Date:
16 October 2017 (online)

Abstract

Polycystic ovary syndrome (PCOS) is a complex disorder which interacts with other genetic and environmental factors to cause dysregulation of steroidogenesis and anovulation as well as insulin resistance. Treatments which address the long-term effects of this unique combination of reproductive and metabolic dysfunction are needed. Over the past decade, new insights into the genetic factors of PCOS and biotechnological advances have led to potential treatments for women with PCOS. These treatments include both new potent pharmaceutical compounds and repurposed drugs which target different steps in metabolic-reproductive pathways to improve long-term health of women with PCOS. These new therapies target key enzymes involved in steroidogenesis, regulatory pathways of gonadotropin secretion, or lower oxidative stress. We review in this article the current common treatments of PCOS, recent developments in the field, and current information on the mode of action, efficacy, and safety of emerging therapeutic compounds.

 
  • References

  • 1 Legro RS, Arslanian SA, Ehrmann DA. , et al; Endocrine Society. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2013; 98 (12) 4565-4592
  • 2 Escobar-Morreale HF, Carmina E, Dewailly D. , et al. Epidemiology, diagnosis and management of hirsutism: a consensus statement by the Androgen Excess and Polycystic Ovary Syndrome Society. Hum Reprod Update 2012; 18 (02) 146-170
  • 3 Venturoli S, Marescalchi O, Colombo FM. , et al. A prospective randomized trial comparing low dose flutamide, finasteride, ketoconazole, and cyproterone acetate-estrogen regimens in the treatment of hirsutism. J Clin Endocrinol Metab 1999; 84 (04) 1304-1310
  • 4 Guido M, Romualdi D, Giuliani M. , et al. Drospirenone for the treatment of hirsute women with polycystic ovary syndrome: a clinical, endocrinological, metabolic pilot study. J Clin Endocrinol Metab 2004; 89 (06) 2817-2823
  • 5 Batukan C, Muderris II. Efficacy of a new oral contraceptive containing drospirenone and ethinyl estradiol in the long-term treatment of hirsutism. Fertil Steril 2006; 85 (02) 436-440
  • 6 Reed SD, Newton KM, Garcia RL. , et al. Complex hyperplasia with and without atypia: clinical outcomes and implications of progestin therapy. Obstet Gynecol 2010; 116 (2, Pt 1): 365-373
  • 7 Knowler WC, Barrett-Connor E, Fowler SE. , et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346 (06) 393-403
  • 8 Baillargeon JP, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril 2004; 82 (04) 893-902
  • 9 Nieuwenhuis-Ruifrok AE, Kuchenbecker WK, Hoek A, Middleton P, Norman RJ. Insulin sensitizing drugs for weight loss in women of reproductive age who are overweight or obese: systematic review and meta-analysis. Hum Reprod Update 2009; 15 (01) 57-68
  • 10 Kocer D, Bayram F, Diri H. The effects of metformin on endothelial dysfunction, lipid metabolism and oxidative stress in women with polycystic ovary syndrome. Gynecol Endocrinol 2014; 30 (05) 367-371
  • 11 Tang T, Glanville J, Hayden CJ, White D, Barth JH, Balen AH. Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study. Hum Reprod 2006; 21 (01) 80-89
  • 12 Ng EH, Wat NM, Ho PC. Effects of metformin on ovulation rate, hormonal and metabolic profiles in women with clomiphene-resistant polycystic ovaries: a randomized, double-blinded placebo-controlled trial. Hum Reprod 2001; 16 (08) 1625-1631
  • 13 Morin-Papunen L, Vauhkonen I, Koivunen R, Ruokonen A, Martikainen H, Tapanainen JS. Metformin versus ethinyl estradiol-cyproterone acetate in the treatment of nonobese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2003; 88 (01) 148-156
  • 14 Cosma M, Swiglo BA, Flynn DN. , et al. Clinical review: insulin sensitizers for the treatment of hirsutism: a systematic review and metaanalyses of randomized controlled trials. J Clin Endocrinol Metab 2008; 93 (04) 1135-1142
  • 15 Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Martikainen HK, Tapanainen JS. Endocrine and metabolic effects of metformin versus ethinyl estradiol-cyproterone acetate in obese women with polycystic ovary syndrome: a randomized study. J Clin Endocrinol Metab 2000; 85 (09) 3161-3168
  • 16 Tang T, Lord JM, Norman RJ, Yasmin E, Balen AH. Insulin-sensitising drugs (metformin, rosiglitazone, pioglitazone, D-chiro-inositol) for women with polycystic ovary syndrome, oligo amenorrhoea and subfertility. Cochrane Database Syst Rev 2012; (05) CD003053
  • 17 Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338 (26) 1876-1880
  • 18 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 2000; 85 (08) 2767-2774
  • 19 Hoeger KM, Kochman L, Wixom N, Craig K, Miller RK, Guzick DS. A randomized, 48-week, placebo-controlled trial of intensive lifestyle modification and/or metformin therapy in overweight women with polycystic ovary syndrome: a pilot study. Fertil Steril 2004; 82 (02) 421-429
  • 20 Wassmann S, Laufs U, Müller K. , et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol 2002; 22 (02) 300-305
  • 21 Collins R, Armitage J, Parish S, Sleigh P, Peto R. ; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361 (9374): 2005-2016
  • 22 Shepherd J, Cobbe SM, Ford I. , et al; West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333 (20) 1301-1307
  • 23 Goldfine AB. Statins: is it really time to reassess benefits and risks?. N Engl J Med 2012; 366 (19) 1752-1755
  • 24 Gazzerro P, Proto MC, Gangemi G. , et al. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 2012; 64 (01) 102-146
  • 25 Corsini A, Mazzotti M, Raiteri M. , et al. Relationship between mevalonate pathway and arterial myocyte proliferation: in vitro studies with inhibitors of HMG-CoA reductase. Atherosclerosis 1993; 101 (01) 117-125
  • 26 Uzzan B, Cohen R, Nicolas P, Cucherat M, Perret GY. Effects of statins on bone mineral density: a meta-analysis of clinical studies. Bone 2007; 40 (06) 1581-1587
  • 27 Hughes A, Rogers MJ, Idris AI, Crockett JC. A comparison between the effects of hydrophobic and hydrophilic statins on osteoclast function in vitro and ovariectomy-induced bone loss in vivo. Calcif Tissue Int 2007; 81 (05) 403-413
  • 28 Ortega I, Cress AB, Wong DH. , et al. Simvastatin reduces steroidogenesis by inhibiting Cyp17a1 gene expression in rat ovarian theca-interstitial cells. Biol Reprod 2012; 86 (01) 1-9
  • 29 Zhang FL, Casey PJ. Protein prenylation: molecular mechanisms and functional consequences. Annu Rev Biochem 1996; 65: 241-269
  • 30 Zhang FL, Casey PJ. Influence of metal ions on substrate binding and catalytic activity of mammalian protein geranylgeranyl transferase type-I. Biochem J 1996; 320 (Pt 3): 925-932
  • 31 Wu CH, Chen YF, Wang JY. , et al. Mutant K-ras oncogene regulates steroidogenesis of normal human adrenocortical cells by the RAF-MEK-MAPK pathway. Br J Cancer 2002; 87 (09) 1000-1005
  • 32 Tee MK, Dong Q, Miller WL. Pathways leading to phosphorylation of p450c17 and to the posttranslational regulation of androgen biosynthesis. Endocrinology 2008; 149 (05) 2667-2677
  • 33 Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J 2010; 74 (05) 818-826
  • 34 Shishehbor MH, Brennan ML, Aviles RJ. , et al. Statins promote potent systemic antioxidant effects through specific inflammatory pathways. Circulation 2003; 108 (04) 426-431
  • 35 Sathyapalan T, Shepherd J, Coady AM, Kilpatrick ES, Atkin SL. Atorvastatin reduces malondialdehyde concentrations in patients with polycystic ovary syndrome. J Clin Endocrinol Metab 2012; 97 (11) 3951-3955
  • 36 Lüftjohann D, Sigit JI, Locatelli S, von Bergmann K, Schmidt HH. High-dose simvastin (80 mg/day) decreases plasma concentrations of total homocyst(e)ine in patients with hypercholesteromia. Atherosclerosis 2001; 155 (01) 265-266
  • 37 Dicker-Brown A, Fonseca VA, Fink LM, Kern PA. The effect of glucose and insulin on the activity of methylene tetrahydrofolate reductase and cystathionine-beta-synthase: studies in hepatocytes. Atherosclerosis 2001; 158 (02) 297-301
  • 38 Sathyapalan T, Shepherd J, Arnett C, Coady AM, Kilpatrick ES, Atkin SL. Atorvastatin increases 25-hydroxy vitamin D concentrations in patients with polycystic ovary syndrome. Clin Chem 2010; 56 (11) 1696-1700
  • 39 Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 2004; 79 (03) 362-371
  • 40 Yildizhan R, Kurdoglu M, Adali E. , et al. Serum 25-hydroxyvitamin D concentrations in obese and non-obese women with polycystic ovary syndrome. Arch Gynecol Obstet 2009; 280 (04) 559-563
  • 41 Wehr E, Pilz S, Schweighofer N. , et al. Association of hypovitaminosis D with metabolic disturbances in polycystic ovary syndrome. Eur J Endocrinol 2009; 161 (04) 575-582
  • 42 Pal L, Zhang H, Williams J. , et al; Reproductive Medicine Network. 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 (08) 3027-3035
  • 43 Rzepczynska IJ, Piotrowski PC, Wong DH, Cress AB, Villanueva J, Duleba AJ. Role of isoprenylation in simvastatin-induced inhibition of ovarian theca-interstitial growth in the rat. Biol Reprod 2009; 81 (05) 850-855
  • 44 Izquierdo D, Foyouzi N, Kwintkiewicz J, Duleba AJ. Mevastatin inhibits ovarian theca-interstitial cell proliferation and steroidogenesis. Fertil Steril 2004; 82 (Suppl. 03) 1193-1197
  • 45 Engelhardt H, Gore-Langton RE, Armstrong DT. Mevinolin (lovastatin) inhibits androstenedione production by porcine ovarian theca cells at the level of the 17 α-hydroxylase:C-17,20-lyase complex. Endocrinology 1989; 124 (05) 2297-2304
  • 46 Duleba AJ, Banaszewska B, Spaczynski RZ, Pawelczyk L. Simvastatin improves biochemical parameters in women with polycystic ovary syndrome: results of a prospective, randomized trial. Fertil Steril 2006; 85 (04) 996-1001
  • 47 Banaszewska B, Pawelczyk L, Spaczynski RZ, Duleba AJ. Comparison of simvastatin and metformin in treatment of polycystic ovary syndrome: prospective randomized trial. J Clin Endocrinol Metab 2009; 94 (12) 4938-4945
  • 48 Banaszewska B, Pawelczyk L, Spaczynski RZ, Dziura J, Duleba AJ. Effects of simvastatin and oral contraceptive agent on polycystic ovary syndrome: prospective, randomized, crossover trial. J Clin Endocrinol Metab 2007; 92 (02) 456-461
  • 49 Banaszewska B, Pawelczyk L, Spaczynski RZ, Duleba AJ. Effects of simvastatin and metformin on polycystic ovary syndrome after six months of treatment. J Clin Endocrinol Metab 2011; 96 (11) 3493-3501
  • 50 Sathyapalan T, Smith KA, Coady A-M, Kilpatrick ES, Atkin SL. Atorvastatin therapy decreases androstenedione and dehydroepiandrosterone sulphate concentrations in patients with polycystic ovary syndrome: randomized controlled study. Ann Clin Biochem 2012; 49 (Pt 1): 80-85
  • 51 Ide H, Fujiya S, Aanuma Y, Agishi Y. Effects of simvastatin, an HMG-CoA reductase inhibitor, on plasma lipids and steroid hormones. Clin Ther 1990; 12 (05) 410-420
  • 52 Yang B, Sun ZJ, Chen B. , et al. Statin ameliorates endothelial dysfunction and insulin resistance in Tibet women with polycystic ovary syndrome. Eur Rev Med Pharmacol Sci 2016; 20 (06) 1185-1191
  • 53 Raja-Khan N, Kunselman AR, Hogeman CS, Stetter CM, Demers LM, Legro RS. Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial. Fertil Steril 2011; 95 (05) 1849-1852
  • 54 Sathyapalan T, Kilpatrick ES, Coady A-M, Atkin SL. The effect of atorvastatin in patients with polycystic ovary syndrome: a randomized double-blind placebo-controlled study. J Clin Endocrinol Metab 2009; 94 (01) 103-108
  • 55 Kaya C, Cengiz SD, Berker B, Demirtaş S, Cesur M, Erdoğan G. Comparative effects of atorvastatin and simvastatin on the plasma total homocysteine levels in women with polycystic ovary syndrome: a prospective randomized study. Fertil Steril 2009; 92 (02) 635-642
  • 56 Krysiak R, Okopien B. Lymphocyte-suppressing and systemic anti-inflammatory effects of high-dose metformin in simvastatin-treated patients with impaired fasting glucose. Atherosclerosis 2012; 225 (02) 403-407
  • 57 Sattar N, Preiss D, Murray HM. , et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375 (9716): 735-742
  • 58 Kazerooni T, Shojaei-Baghini A, Dehbashi S, Asadi N, Ghaffarpasand F, Kazerooni Y. Effects of metformin plus simvastatin on polycystic ovary syndrome: a prospective, randomized, double-blind, placebo-controlled study. Fertil Steril 2010; 94 (06) 2208-2213
  • 59 Sathyapalan T, Kilpatrick ES, Coady AM, Atkin SL. Atorvastatin pretreatment augments the effect of metformin in patients with polycystic ovary syndrome (PCOS). Clin Endocrinol (Oxf) 2010; 72 (04) 566-568
  • 60 Gao L, Zhao FL, Li SC. Statin is a reasonable treatment option for patients with polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Exp Clin Endocrinol Diabetes 2012; 120 (06) 367-375
  • 61 Sun J, Yuan Y, Cai R. , et al. An investigation into the therapeutic effects of statins with metformin on polycystic ovary syndrome: a meta-analysis of randomised controlled trials. BMJ Open 2015; 5 (03) e007280
  • 62 Raval AD, Hunter T, Stuckey B, Hart RJ. Statins for women with polycystic ovary syndrome not actively trying to conceive. Cochrane Database Syst Rev 2011; (10) CD008565
  • 63 Azargoon A, Ghorbani R, Faraji Z. Effects of simvastatin pretreatment on clomiphene response in clomiphene-resistant women with polycystic ovary syndrome. J Family Reprod Health 2013; 7 (04) 165-170
  • 64 Rocco MB. Statins and diabetes risk: fact, fiction, and clinical implications. Cleve Clin J Med 2012; 79 (12) 883-893
  • 65 Cariou B, van Harmelen K, Duran-Sandoval D. , et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 2006; 281 (16) 11039-11049
  • 66 Koh KK, Quon MJ, Han SH. , et al. Differential metabolic effects of pravastatin and simvastatin in hypercholesterolemic patients. Atherosclerosis 2009; 204 (02) 483-490
  • 67 Puurunen J, Piltonen T, Puukka K. , 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 2013; 98 (12) 4798-4807
  • 68 Satake H, Aoyama M, Sekiguchi T, Kawada T. Insight into molecular and functional diversity of tachykinins and their receptors. Protein Pept Lett 2013; 20 (06) 615-627
  • 69 Satake H, Kawada T. Overview of the primary structure, tissue-distribution, and functions of tachykinins and their receptors. Curr Drug Targets 2006; 7 (08) 963-974
  • 70 Maeda K, Ohkura S, Uenoyama Y. , et al. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Brain Res 2010; 1364: 103-115
  • 71 Goodman RL, Hileman SM, Nestor CC. , et al. Kisspeptin, neurokinin B, and dynorphin act in the arcuate nucleus to control activity of the GnRH pulse generator in ewes. Endocrinology 2013; 154 (11) 4259-4269
  • 72 Topaloglu AK, Reimann F, Guclu M. , et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet 2009; 41 (03) 354-358
  • 73 Choe HK, Kim HD, Park SH. , et al. Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation. Proc Natl Acad Sci U S A 2013; 110 (14) 5677-5682
  • 74 Krajewski SJ, Anderson MJ, Iles-Shih L, Chen KJ, Urbanski HF, Rance NE. Morphologic evidence that neurokinin B modulates gonadotropin-releasing hormone secretion via neurokinin 3 receptors in the rat median eminence. J Comp Neurol 2005; 489 (03) 372-386
  • 75 Amstalden M, Coolen LM, Hemmerle AM. , et al. Neurokinin 3 receptor immunoreactivity in the septal region, preoptic area and hypothalamus of the female sheep: colocalisation in neurokinin B cells of the arcuate nucleus but not in gonadotrophin-releasing hormone neurones. J Neuroendocrinol 2010; 22 (01) 1-12
  • 76 Guran T, Tolhurst G, Bereket A. , et al. Hypogonadotropic hypogonadism due to a novel missense mutation in the first extracellular loop of the neurokinin B receptor. J Clin Endocrinol Metab 2009; 94 (10) 3633-3639
  • 77 García-Ortega J, Pinto FM, Fernández-Sánchez M. , et al. Expression of neurokinin B/NK3 receptor and kisspeptin/KISS1 receptor in human granulosa cells. Hum Reprod 2014; 29 (12) 2736-2746
  • 78 Cejudo Roman A, Pinto FM, Dorta I. , et al. Analysis of the expression of neurokinin B, kisspeptin, and their cognate receptors NK3R and KISS1R in the human female genital tract. Fertil Steril 2012; 97 (05) 1213-1219
  • 79 Pintado CO, Pinto FM, Pennefather JN. , et al. A role for tachykinins in female mouse and rat reproductive function. Biol Reprod 2003; 69 (03) 940-946
  • 80 Ghosh P, Saha SK, Bhattacharya S, Bhattacharya S, Mukherjee S, Roy SS. Tachykinin family genes and their receptors are differentially expressed in the hypothyroid ovary and pituitary. Cell Physiol Biochem 2007; 20 (05) 357-368
  • 81 Fraser GL, Ramael S, Hoveyda HR, Gheyle L, Combalbert J. The NK3 receptor antagonist ESN364 suppresses sex hormones in men and women. J Clin Endocrinol Metab 2016; 101 (02) 417-426
  • 82 Page NM, Dakour J, Morrish DW. Gene regulation of neurokinin B and its receptor NK3 in late pregnancy and pre-eclampsia. Mol Hum Reprod 2006; 12 (07) 427-433
  • 83 Patak EN, Pennefather JN, Story ME. Effects of tachykinins on uterine smooth muscle. Clin Exp Pharmacol Physiol 2000; 27 (11) 922-927
  • 84 Emonds-Alt X, Bichon D, Ducoux JP. , et al. SR 142801, the first potent non-peptide antagonist of the tachykinin NK3 receptor. Life Sci 1995; 56 (01) PL27-PL32
  • 85 Sarau HM, Griswold DE, Potts W. , et al. Nonpeptide tachykinin receptor antagonists: I. Pharmacological and pharmacokinetic characterization of SB 223412, a novel, potent and selective neurokinin-3 receptor antagonist. J Pharmacol Exp Ther 1997; 281 (03) 1303-1311
  • 86 Hoveyda HR, Roy MO, Blanc S. , et al. Discovery of 3-aryl-5-acylpiperazinyl-pyrazoles as antagonists to the NK3 receptor. Bioorg Med Chem Lett 2011; 21 (07) 1991-1996
  • 87 Hoveyda HR, Fraser GL, Roy MO. , et al. Discovery and optimization of novel antagonists to the human neurokinin-3 receptor for the treatment of sex-hormone disorders (Part I). J Med Chem 2015; 58 (07) 3060-3082
  • 88 Hoveyda HR, Fraser GL, Dutheuil G. , et al. Optimization of novel antagonists to the neurokinin-3 receptor for the treatment of sex-hormone disorders (Part II). ACS Med Chem Lett 2015; 6 (07) 736-740
  • 89 Fraser GL, Hoveyda HR, Clarke IJ. , et al. The NK3 receptor antagonist ESN364 interrupts pulsatile LH secretion and moderates levels of ovarian hormones throughout the menstrual cycle. Endocrinology 2015; 156 (11) 4214-4225
  • 90 Litman RE, Smith MA, Desai DG, Simpson T, Sweitzer D, Kanes SJ. The selective neurokinin 3 antagonist AZD2624 does not improve symptoms or cognition in schizophrenia: a proof-of-principle study. J Clin Psychopharmacol 2014; 34 (02) 199-204
  • 91 Li Y, Zhou D, Ferguson SS, Dorff P, Simpson TR, Grimm SW. In vitro assessment of metabolic drug–drug interaction potential of AZD2624, neurokinin-3 receptor antagonist, through cytochrome P(450) enzyme identification, inhibition, and induction studies. Xenobiotica 2010; 40 (11) 721-729
  • 92 Qi X, Salem M, Zhou W. , et al. Neurokinin B exerts direct effects on the ovary to stimulate estradiol production. Endocrinology 2016; 157 (09) 3355-3365
  • 93 Laoharatchatathanin T, Terashima R, Yonezawa T, Kurusu S, Kawaminami M. Augmentation of metastin/kisspeptin mRNA expression by the proestrous luteinizing hormone surge in granulosa cells of rats: implications for luteinization. Biol Reprod 2015; 93 (01) 15
  • 94 Simpson TR, Gadient R, Li Y. Discovery of AZD2624: a potent and selective NK3 antagonist to test the NK3 hypothesis in schizophrenia. Abstracts of Papers, 239th ACS National Meeting. March 21–25, 2010. San Francisco, CA
  • 95 George JT, Kakkar R, Marshall J. , et al. Neurokinin B receptor antagonism in women with polycystic ovary syndrome: a randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (11) 4313-4321
  • 96 Navarro VM, Fernández-Fernández R, Nogueiras R. , et al. Novel role of 26RFa, a hypothalamic RFamide orexigenic peptide, as putative regulator of the gonadotropic axis. J Physiol 2006; 573 (Pt 1): 237-249
  • 97 Wolfe A, Wu S. Estrogen receptor-β in the gonadotropin-releasing hormone neuron. Semin Reprod Med 2012; 30 (01) 23-31
  • 98 Navarro VM, Ruiz-Pino F, Sánchez-Garrido MA. , et al. Role of neurokinin B in the control of female puberty and its modulation by metabolic status. J Neurosci 2012; 32 (07) 2388-2397
  • 99 Lee JH, Miele ME, Hicks DJ. , et al. KiSS-1, a novel human malignant melanoma metastasis-suppressor gene. J Natl Cancer Inst 1996; 88 (23) 1731-1737
  • 100 West A, Vojta PJ, Welch DR, Weissman BE. Chromosome localization and genomic structure of the KiSS-1 metastasis suppressor gene (KISS1). Genomics 1998; 54 (01) 145-148
  • 101 Kotani M, Detheux M, Vandenbogaerde A. , et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan G protein-coupled receptor GPR54. J Biol Chem 2001; 276 (37) 34631-34636
  • 102 Gottsch ML, Clifton DK, Steiner RA. From KISS1 to kisspeptins: an historical perspective and suggested nomenclature. Peptides 2009; 30 (01) 4-9
  • 103 Lehman MN, Robinson JE, Karsch FJ, Silverman AJ. Immunocytochemical localization of luteinizing hormone-releasing hormone (LHRH) pathways in the sheep brain during anestrus and the mid-luteal phase of the estrous cycle. J Comp Neurol 1986; 244 (01) 19-35
  • 104 Rometo AM, Krajewski SJ, Voytko ML, Rance NE. Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys. J Clin Endocrinol Metab 2007; 92 (07) 2744-2750
  • 105 Vida B, Deli L, Hrabovszky E. , et al. Evidence for suprachiasmatic vasopressin neurones innervating kisspeptin neurones in the rostral periventricular area of the mouse brain: regulation by oestrogen. J Neuroendocrinol 2010; 22 (09) 1032-1039
  • 106 Zhang C, Roepke TA, Kelly MJ, Rønnekleiv OK. Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. J Neurosci 2008; 28 (17) 4423-4434
  • 107 Young J, George JT, Tello JA. , et al. Kisspeptin restores pulsatile LH secretion in patients with neurokinin B signaling deficiencies: physiological, pathophysiological and therapeutic implications. Neuroendocrinology 2013; 97 (02) 193-202
  • 108 Martínez de la Escalera G, Choi AL, Weiner RI. Generation and synchronization of gonadotropin-releasing hormone (GnRH) pulses: intrinsic properties of the GT1-1 GnRH neuronal cell line. Proc Natl Acad Sci U S A 1992; 89 (05) 1852-1855
  • 109 Terasawa E, Keen KL, Mogi K, Claude P. Pulsatile release of luteinizing hormone-releasing hormone (LHRH) in cultured LHRH neurons derived from the embryonic olfactory placode of the rhesus monkey. Endocrinology 1999; 140 (03) 1432-1441
  • 110 Wakabayashi Y, Yamamura T, Sakamoto K, Mori Y, Okamura H. Electrophysiological and morphological evidence for synchronized GnRH pulse generator activity among Kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in goats. J Reprod Dev 2013; 59 (01) 40-48
  • 111 Ramaswamy S, Seminara SB, Ali B, Ciofi P, Amin NA, Plant TM. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 2010; 151 (09) 4494-4503
  • 112 Chan YM, Butler JP, Sidhoum VF, Pinnell NE, Seminara SB. Kisspeptin administration to women: a window into endogenous kisspeptin secretion and GnRH responsiveness across the menstrual cycle. J Clin Endocrinol Metab 2012; 97 (08) E1458-E1467
  • 113 Shaw ND, Histed SN, Srouji SS, Yang J, Lee H, Hall JE. Estrogen negative feedback on gonadotropin secretion: evidence for a direct pituitary effect in women. J Clin Endocrinol Metab 2010; 95 (04) 1955-1961
  • 114 Roseweir AK, Kauffman AS, Smith JT. , et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J Neurosci 2009; 29 (12) 3920-3929
  • 115 Goodman RL, Coolen LM, Anderson GM. , et al. Evidence that dynorphin plays a major role in mediating progesterone negative feedback on gonadotropin-releasing hormone neurons in sheep. Endocrinology 2004; 145 (06) 2959-2967
  • 116 de Croft S, Boehm U, Herbison AE. Neurokinin B activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology 2013; 154 (08) 2750-2760
  • 117 Smith JT, Dungan HM, Stoll EA. , et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 2005; 146 (07) 2976-2984
  • 118 Piet R, Fraissenon A, Boehm U, Herbison AE. Estrogen permits vasopressin signaling in preoptic kisspeptin neurons in the female mouse. J Neurosci 2015; 35 (17) 6881-6892
  • 119 Smith JT, Popa SM, Clifton DK, Hoffman GE, Steiner RA. Kiss1 neurons in the forebrain as central processors for generating the preovulatory luteinizing hormone surge. J Neurosci 2006; 26 (25) 6687-6694
  • 120 Han SK, Gottsch ML, Lee KJ. , et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J Neurosci 2005; 25 (49) 11349-11356
  • 121 Goodman RL, Lehman MN, Smith JT. , et al. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 2007; 148 (12) 5752-5760
  • 122 Uenoyama Y, Nakamura S, Hayakawa Y. , et al. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats. J Neuroendocrinol 2015; 27 (03) 187-197
  • 123 Beale KE, Kinsey-Jones JS, Gardiner JV. , et al. The physiological role of arcuate kisspeptin neurons in the control of reproductive function in female rats. Endocrinology 2014; 155 (03) 1091-1098
  • 124 Mittelman-Smith MA, Krajewski-Hall SJ, McMullen NT, Rance NE. Ablation of KNDy neurons results in hypogonadotropic hypogonadism and amplifies the steroid-induced LH surge in female rats. Endocrinology 2016; 157 (05) 2015-2027
  • 125 Smith JT, Acohido BV, Clifton DK, Steiner RA. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J Neuroendocrinol 2006; 18 (04) 298-303
  • 126 Farooqi IS, O'Rahilly S. Leptin: a pivotal regulator of human energy homeostasis. Am J Clin Nutr 2009; 89 (03) 980S-984S
  • 127 Mittelman-Smith MA, Williams H, Krajewski-Hall SJ. , et al. Arcuate kisspeptin/neurokinin B/dynorphin (KNDy) neurons mediate the estrogen suppression of gonadotropin secretion and body weight. Endocrinology 2012; 153 (06) 2800-2812
  • 128 Schneider HP, Leyendecker G. The normal and dysregulated human menstrual cycle: current physiological and clinical views. Adv Steroid Biochem Pharmacol 1979; 7: 23-50
  • 129 Young J, Bouligand J, Francou B. , et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J Clin Endocrinol Metab 2010; 95 (05) 2287-2295
  • 130 Dalkin AC, Haisenleder DJ, Ortolano GA, Ellis TR, Marshall JC. The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression. Endocrinology 1989; 125 (02) 917-924
  • 131 de Roux N, Genin E, Carel JC, Matsuda F, Chaussain JL, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci U S A 2003; 100 (19) 10972-10976
  • 132 Li XF, Kinsey-Jones JS, Cheng Y. , et al. Kisspeptin signalling in the hypothalamic arcuate nucleus regulates GnRH pulse generator frequency in the rat. PLoS One 2009; 4 (12) e8334
  • 133 Jayasena CN, Nijher GM, Chaudhri OB. , et al. Subcutaneous injection of kisspeptin-54 acutely stimulates gonadotropin secretion in women with hypothalamic amenorrhea, but chronic administration causes tachyphylaxis. J Clin Endocrinol Metab 2009; 94 (11) 4315-4323
  • 134 Jayasena CN, Abbara A, Veldhuis JD. , et al. Increasing LH pulsatility in women with hypothalamic amenorrhoea using intravenous infusion of Kisspeptin-54. J Clin Endocrinol Metab 2014; 99 (06) E953-E961
  • 135 Scott G, Ahmad I, Howard K. , et al. Double-blind, randomized, placebo-controlled study of safety, tolerability, pharmacokinetics and pharmacodynamics of TAK-683, an investigational metastin analogue in healthy men. Br J Clin Pharmacol 2013; 75 (02) 381-391
  • 136 Jayasena CN, Comninos AN, Veldhuis JD. , et al. A single injection of kisspeptin-54 temporarily increases luteinizing hormone pulsatility in healthy women. Clin Endocrinol (Oxf) 2013; 79 (04) 558-563
  • 137 Jayasena CN, Comninos AN, Nijher GM. , et al. Twice-daily subcutaneous injection of kisspeptin-54 does not abolish menstrual cyclicity in healthy female volunteers. J Clin Endocrinol Metab 2013; 98 (11) 4464-4474
  • 138 Jayasena CN, Abbara A, Comninos AN. , et al. Kisspeptin-54 triggers egg maturation in women undergoing in vitro fertilization. J Clin Invest 2014; 124 (08) 3667-3677
  • 139 George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clin Endocrinol (Oxf) 2013; 79 (01) 100-104
  • 140 Castellano JM, Navarro VM, Fernández-Fernández R. , et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 2005; 146 (09) 3917-3925
  • 141 Seminara SB, Dipietro MJ, Ramaswamy S, Crowley Jr WF, Plant TM. Continuous human metastin 45-54 infusion desensitizes G protein-coupled receptor 54-induced gonadotropin-releasing hormone release monitored indirectly in the juvenile male Rhesus monkey (Macaca mulatta): a finding with therapeutic implications. Endocrinology 2006; 147 (05) 2122-2126
  • 142 Ramaswamy S, Seminara SB, Pohl CR, DiPietro MJ, Crowley Jr WF, Plant TM. Effect of continuous intravenous administration of human metastin 45-54 on the neuroendocrine activity of the hypothalamic-pituitary-testicular axis in the adult male rhesus monkey (Macaca mulatta). Endocrinology 2007; 148 (07) 3364-3370
  • 143 Scott E, Steward WP, Gescher AJ, Brown K. Resveratrol in human cancer chemoprevention--choosing the ‘right’ dose. Mol Nutr Food Res 2012; 56 (01) 7-13
  • 144 Wu Y, Jia LL, Zheng YN. , et al. Resveratrate protects human skin from damage due to repetitive ultraviolet irradiation. J Eur Acad Dermatol Venereol 2013; 27 (03) 345-350
  • 145 Magyar K, Halmosi R, Palfi A. , et al. Cardioprotection by resveratrol: a human clinical trial in patients with stable coronary artery disease. Clin Hemorheol Microcirc 2012; 50 (03) 179-187
  • 146 Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL. Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One 2011; 6 (12) e29102
  • 147 Wood JG, Rogina B, Lavu S. , et al. Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature 2004; 430 (7000): 686-689
  • 148 Bass TM, Weinkove D, Houthoofd K, Gems D, Partridge L. Effects of resveratrol on lifespan in Drosophila melanogaster and Caenorhabditis elegans. Mech Ageing Dev 2007; 128 (10) 546-552
  • 149 Gerhardt E, Gräber S, Szego EM. , et al. Idebenone and resveratrol extend lifespan and improve motor function of HtrA2 knockout mice. PLoS One 2011; 6 (12) e28855
  • 150 Mao Z, Hine C, Tian X. , et al. SIRT6 promotes DNA repair under stress by activating PARP1. Science 2011; 332 (6036): 1443-1446
  • 151 Qiang L, Lin HV, Kim-Muller JY, Welch CL, Gu W, Accili D. Proatherogenic abnormalities of lipid metabolism in SirT1 transgenic mice are mediated through Creb deacetylation. Cell Metab 2011; 14 (06) 758-767
  • 152 Wong DH, Villanueva JA, Cress AB, Sokalska A, Ortega I, Duleba AJ. Resveratrol inhibits the mevalonate pathway and potentiates the antiproliferative effects of simvastatin in rat theca-interstitial cells. Fertil Steril 2011; 96 (05) 1252-1258
  • 153 Wong DH, Villanueva JA, Cress AB, Duleba AJ. Effects of resveratrol on proliferation and apoptosis in rat ovarian theca-interstitial cells. Mol Hum Reprod 2010; 16 (04) 251-259
  • 154 Ortega I, Villanueva JA, Wong DH. , et al. Resveratrol potentiates effects of simvastatin on inhibition of rat ovarian theca-interstitial cells steroidogenesis. J Ovarian Res 2014; 7: 21
  • 155 Supornsilchai V, Svechnikov K, Seidlova-Wuttke D, Wuttke W, Söder O. Phytoestrogen resveratrol suppresses steroidogenesis by rat adrenocortical cells by inhibiting cytochrome P450 c21-hydroxylase. Horm Res 2005; 64 (06) 280-286
  • 156 Svechnikov K, Spatafora C, Svechnikova I, Tringali C, Söder O. Effects of resveratrol analogs on steroidogenesis and mitochondrial function in rat Leydig cells in vitro. J Appl Toxicol 2009; 29 (08) 673-680
  • 157 Ortega I, Villanueva JA, Wong DH. , et al. Resveratrol reduces steroidogenesis in rat ovarian theca-interstitial cells: the role of inhibition of Akt/PKB signaling pathway. Endocrinology 2012; 153 (08) 4019-4029
  • 158 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
  • 159 Hines GA, Smith ER, Azziz R. Influence of insulin and testosterone on adrenocortical steroidogenesis in vitro: preliminary studies. Fertil Steril 2001; 76 (04) 730-735
  • 160 Banaszewska B, Wrotyńska-Barczyńska J, Spaczynski RZ, Pawelczyk L, Duleba AJ. Effects of resveratrol on polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2016; 101 (11) 4322-4328
  • 161 Faghihzadeh F, Adibi P, Hekmatdoost A. The effects of resveratrol supplementation on cardiovascular risk factors in patients with non-alcoholic fatty liver disease: a randomised, double-blind, placebo-controlled study. Br J Nutr 2015; 114 (05) 796-803
  • 162 Crandall JP, Oram V, Trandafirescu G. , et al. Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci 2012; 67 (12) 1307-1312
  • 163 Ortega I, Wong DH, Villanueva JA. , et al. Effects of resveratrol on growth and function of rat ovarian granulosa cells. Fertil Steril 2012; 98 (06) 1563-1573
  • 164 Cho IJ, Ahn JY, Kim S, Choi MS, Ha TY. Resveratrol attenuates the expression of HMG-CoA reductase mRNA in hamsters. Biochem Biophys Res Commun 2008; 367 (01) 190-194
  • 165 Do GM, Kwon EY, Kim HJ. , et al. Long-term effects of resveratrol supplementation on suppression of atherogenic lesion formation and cholesterol synthesis in apo E-deficient mice. Biochem Biophys Res Commun 2008; 374 (01) 55-59
  • 166 Gnoni GV, Paglialonga G. Resveratrol inhibits fatty acid and triacylglycerol synthesis in rat hepatocytes. Eur J Clin Invest 2009; 39 (03) 211-218
  • 167 Penumathsa SV, Thirunavukkarasu M, Koneru S. , et al. Statin and resveratrol in combination induces cardioprotection against myocardial infarction in hypercholesterolemic rat. J Mol Cell Cardiol 2007; 42 (03) 508-516
  • 168 Villanueva JA, Sokalska A, Cress AB. , et al. Resveratrol potentiates effect of simvastatin on inhibition of mevalonate pathway in human endometrial stromal cells. J Clin Endocrinol Metab 2013; 98 (03) E455-E462
  • 169 Bo S, Ponzo V, Evangelista A. , et al. Effects of 6 months of resveratrol versus placebo on pentraxin 3 in patients with type 2 diabetes mellitus: a double-blind randomized controlled trial. Acta Diabetol 2017; 54 (05) 499-507
  • 170 Korsholm AS, Kjær TN, Ornstrup MJ, Pedersen SB. Comprehensive metabolomic analysis in blood, urine, fat, and muscle in men with metabolic syndrome: a Randomized, placebo-controlled clinical trial on the effects of resveratrol after four months' treatment. Int J Mol Sci 2017; 18 (03) 554
  • 171 Wang F, Zhao Y, Niu Y. , et al. Activated glucose-6-phosphate dehydrogenase is associated with insulin resistance by upregulating pentose and pentosidine in diet-induced obesity of rats. Horm Metab Res 2012; 44 (13) 938-942
  • 172 Kjær TN, Ornstrup MJ, Poulsen MM. , et al. No beneficial effects of resveratrol on the metabolic syndrome: a randomized placebo-controlled clinical trial. J Clin Endocrinol Metab 2017; 102 (05) 1642-1651
  • 173 Olesen J, Gliemann L, Biensø R, Schmidt J, Hellsten Y, Pilegaard H. Exercise training, but not resveratrol, improves metabolic and inflammatory status in skeletal muscle of aged men. J Physiol 2014; 592 (08) 1873-1886
  • 174 Monastra G, Unfer V, Harrath AH, Bizzarri M. Combining treatment with myo-inositol and D-chiro-inositol (40:1) is effective in restoring ovary function and metabolic balance in PCOS patients. Gynecol Endocrinol 2017; 33 (01) 1-9
  • 175 Larner J. D-chiro-inositol--its functional role in insulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 2002; 3 (01) 47-60
  • 176 Larner J, Brautigan DL, Thorner MO. D-chiro-inositol glycans in insulin signaling and insulin resistance. Mol Med 2010; 16 (11-12): 543-552
  • 177 Ortmeyer HK. Dietary myoinositol results in lower urine glucose and in lower postprandial plasma glucose in obese insulin resistant rhesus monkeys. Obes Res 1996; 4 (06) 569-575
  • 178 Sun TH, Heimark DB, Nguygen T, Nadler JL, Larner J. Both myo-inositol to chiro-inositol epimerase activities and chiro-inositol to myo-inositol ratios are decreased in tissues of GK type 2 diabetic rats compared to Wistar controls. Biochem Biophys Res Commun 2002; 293 (03) 1092-1098
  • 179 Baillargeon JP, Iuorno MJ, Jakubowicz DJ, Apridonidze T, He N, Nestler JE. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2004; 89 (01) 242-249
  • 180 Janovick JA, Conn PM. Gonadotropin-releasing hormone (GnRH)-receptor coupling to inositol phosphate and prolactin production in GH3 cells stably transfected with rat GnRH receptor complementary deoxyribonucleic acid. Endocrinology 1994; 135 (05) 2214-2219
  • 181 Nestler JE, Unfer V. Reflections on inositol(s) for PCOS therapy: steps toward success. Gynecol Endocrinol 2015; 31 (07) 501-505
  • 182 Goud PT, Goud AP, Van Oostveldt P, Dhont M. Presence and dynamic redistribution of type I inositol 1,4,5-trisphosphate receptors in human oocytes and embryos during in-vitro maturation, fertilization and early cleavage divisions. Mol Hum Reprod 1999; 5 (05) 441-451
  • 183 Nestler JE. Insulin and insulin-like growth factor-I stimulate the 3 beta-hydroxysteroid dehydrogenase activity of human placental cytotrophoblasts. Endocrinology 1989; 125 (04) 2127-2133
  • 184 Unfer V, Carlomagno G, Papaleo E, Vailati S, Candiani M, Baillargeon JP. Hyperinsulinemia alters myoinositol to d-chiroinositol ratio in the follicular fluid of patients with PCOS. Reprod Sci 2014; 21 (07) 854-858
  • 185 Chiu TT, Rogers MS, Law EL, Briton-Jones CM, Cheung LP, Haines CJ. Follicular fluid and serum concentrations of myo-inositol in patients undergoing IVF: relationship with oocyte quality. Hum Reprod 2002; 17 (06) 1591-1596
  • 186 Carlomagno G, Unfer V, Roseff S. The D-chiro-inositol paradox in the ovary. Fertil Steril 2011; 95 (08) 2515-2516
  • 187 Heimark D, McAllister J, Larner J. Decreased myo-inositol to chiro-inositol (M/C) ratios and increased M/C epimerase activity in PCOS theca cells demonstrate increased insulin sensitivity compared to controls. Endocr J 2014; 61 (02) 111-117
  • 188 Baillargeon JP, Iuorno MJ, Apridonidze T, Nestler JE. Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women with polycystic ovary syndrome. Metab Syndr Relat Disord 2010; 8 (02) 127-136
  • 189 Vucenik I, Ramakrishna G, Tantivejkul K, Anderson LM, Ramljak D. Inositol hexaphosphate (IP6) blocks proliferation of human breast cancer cells through a PKCdelta-dependent increase in p27Kip1 and decrease in retinoblastoma protein (pRb) phosphorylation. Breast Cancer Res Treat 2005; 91 (01) 35-45
  • 190 Michell RH. Inositol derivatives: evolution and functions. Nat Rev Mol Cell Biol 2008; 9 (02) 151-161
  • 191 Ortega HH, Salvetti NR, Müller LA. , et al. Characterization of cytoskeletal proteins in follicular structures of cows with cystic ovarian disease. J Comp Pathol 2007; 136 (04) 222-230
  • 192 Genazzani AD, Lanzoni C, Ricchieri F, Jasonni VM. Myo-inositol administration positively affects hyperinsulinemia and hormonal parameters in overweight patients with polycystic ovary syndrome. Gynecol Endocrinol 2008; 24 (03) 139-144
  • 193 Gerli S, Mignosa M, Di Renzo GC. Effects of inositol on ovarian function and metabolic factors in women with PCOS: a randomized double blind placebo-controlled trial. Eur Rev Med Pharmacol Sci 2003; 7 (06) 151-159
  • 194 Lisi F, Carfagna P, Oliva MM. , et al. Pretreatment with myo-inositol in non polycystic ovary syndrome patients undergoing multiple follicular stimulation for IVF: a pilot study. Reprod Biol Endocrinol 2012; 10: 52
  • 195 Morgante G, Orvieto R, Di Sabatino A, Musacchio MC, De Leo V. The role of inositol supplementation in patients with polycystic ovary syndrome, with insulin resistance, undergoing the low-dose gonadotropin ovulation induction regimen. Fertil Steril 2011; 95 (08) 2642-2644
  • 196 Kamenov Z, Kolarov G, Gateva A, Carlomagno G, Genazzani AD. Ovulation induction with myo-inositol alone and in combination with clomiphene citrate in polycystic ovarian syndrome patients with insulin resistance. Gynecol Endocrinol 2015; 31 (02) 131-135
  • 197 Minozzi M, Costantino D, Guaraldi C, Unfer V. The effect of a combination therapy with myo-inositol and a combined oral contraceptive pill versus a combined oral contraceptive pill alone on metabolic, endocrine, and clinical parameters in polycystic ovary syndrome. Gynecol Endocrinol 2011; 27 (11) 920-924
  • 198 Zacchè MM, Caputo L, Filippis S, Zacchè G, Dindelli M, Ferrari A. Efficacy of myo-inositol in the treatment of cutaneous disorders in young women with polycystic ovary syndrome. Gynecol Endocrinol 2009; 25 (08) 508-513
  • 199 Iuorno MJ, Jakubowicz DJ, Baillargeon JP. , et al. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Endocr Pract 2002; 8 (06) 417-423
  • 200 Nestler JE, Jakubowicz DJ, Reamer P, Gunn RD, Allan G. Ovulatory and metabolic effects of D-chiro-inositol in the polycystic ovary syndrome. N Engl J Med 1999; 340 (17) 1314-1320
  • 201 Isabella R, Raffone E. Does ovary need D-chiro-inositol?. J Ovarian Res 2012; 5 (01) 14
  • 202 Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab 1998; 83 (06) 2001-2005
  • 203 Facchinetti F, Bizzarri M, Benvenga S. , et al. Results from the International Consensus Conference on Myo-inositol and d-chiro-inositol in Obstetrics and Gynecology: the link between metabolic syndrome and PCOS. Eur J Obstet Gynecol Reprod Biol 2015; 195: 72-76
  • 204 Colazingari S, Treglia M, Najjar R, Bevilacqua A. The combined therapy myo-inositol plus D-chiro-inositol, rather than D-chiro-inositol, is able to improve IVF outcomes: results from a randomized controlled trial. Arch Gynecol Obstet 2013; 288 (06) 1405-1411
  • 205 Nordio M, Proietti E. The combined therapy with myo-inositol and D-chiro-inositol reduces the risk of metabolic disease in PCOS overweight patients compared to myo-inositol supplementation alone. Eur Rev Med Pharmacol Sci 2012; 16 (05) 575-581
  • 206 Gerli S, Papaleo E, Ferrari A, Di Renzo GC. Randomized, double blind placebo-controlled trial: effects of myo-inositol on ovarian function and metabolic factors in women with PCOS. Eur Rev Med Pharmacol Sci 2007; 11 (05) 347-354
  • 207 Artini PG, Di Berardino OM, Papini F. , et al. Endocrine and clinical effects of myo-inositol administration in polycystic ovary syndrome. A randomized study. Gynecol Endocrinol 2013; 29 (04) 375-379
  • 208 Tagliaferri V, Romualdi D, Immediata V. , et al. Metformin vs myoinositol: which is better in obese polycystic ovary syndrome patients? A randomized controlled crossover study. Clin Endocrinol (Oxf) 2017; 86 (05) 725-730
  • 209 Cavalli P, Copp AJ. Inositol and folate resistant neural tube defects. J Med Genet 2002; 39 (02) E5
  • 210 Vink JM, Sadrzadeh S, Lambalk CB, Boomsma DI. Heritability of polycystic ovary syndrome in a Dutch twin-family study. J Clin Endocrinol Metab 2006; 91 (06) 2100-2104
  • 211 Chen ZJ, Zhao H, He L. , et al. Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Nat Genet 2011; 43 (01) 55-59
  • 212 Shi Y, Zhao H, Shi Y. , et al. Genome-wide association study identifies eight new risk loci for polycystic ovary syndrome. Nat Genet 2012; 44 (09) 1020-1025
  • 213 Lerchbaum E, Trummer O, Giuliani A, Gruber HJ, Pieber TR, Obermayer-Pietsch B. Susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21, and 9q33.3 in a cohort of Caucasian women. Horm Metab Res 2011; 43 (11) 743-747
  • 214 Goodarzi MO, Jones MR, Li X. , et al. Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. J Med Genet 2012; 49 (02) 90-95
  • 215 Welt CK, Styrkarsdottir U, Ehrmann DA. , et al. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol Metab 2012; 97 (07) E1342-E1347
  • 216 Eriksen MB, Brusgaard K, Andersen M. , et al. Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis. Eur J Obstet Gynecol Reprod Biol 2012; 163 (01) 39-42
  • 217 Louwers YV, Stolk L, Uitterlinden AG, Laven JS. Cross-ethnic meta-analysis of genetic variants for polycystic ovary syndrome. J Clin Endocrinol Metab 2013; 98 (12) E2006-E2012
  • 218 Zhang HY, Zhang YF, Han YK, Xue FX, Zhao XH, Zhang XL. [Activation and significance of the PI3K/Akt pathway in endometrium with polycystic ovary syndrome patients]. Zhonghua Fu Chan Ke Za Zhi 2012; 47 (01) 19-23
  • 219 Munir I, Yen HW, Geller DH. , et al. Insulin augmentation of 17alpha-hydroxylase activity is mediated by phosphatidyl inositol 3-kinase but not extracellular signal-regulated kinase-1/2 in human ovarian theca cells. Endocrinology 2004; 145 (01) 175-183
  • 220 Ciaraldi TP. Molecular defects of insulin action in the polycystic ovary syndrome: possible tissue specificity. J Pediatr Endocrinol Metab 2000; 13 (Suppl. 05) 1291-1293
  • 221 Kosova G, Urbanek M. Genetics of the polycystic ovary syndrome. Mol Cell Endocrinol 2013; 373 (1-2): 29-38
  • 222 Marat AL, Dokainish H, McPherson PS. DENN domain proteins: regulators of Rab GTPases. J Biol Chem 2011; 286 (16) 13791-13800
  • 223 McAllister JM, Legro RS, Modi BP, Strauss III JF. Functional genomics of PCOS: from GWAS to molecular mechanisms. Trends Endocrinol Metab 2015; 26 (03) 118-124
  • 224 Nagase T, Kikuno R, Ohara O. Prediction of the coding sequences of unidentified human genes. XXII. The complete sequences of 50 new cDNA clones which code for large proteins. DNA Res 2001; 8 (06) 319-327
  • 225 Strauss III JF, McAllister JM, Urbanek M. Persistence pays off for PCOS gene prospectors. J Clin Endocrinol Metab 2012; 97 (07) 2286-2288
  • 226 Wood JR, Ho CK, Nelson-Degrave VL, McAllister JM, Strauss III JF. The molecular signature of polycystic ovary syndrome (PCOS) theca cells defined by gene expression profiling. J Reprod Immunol 2004; 63 (01) 51-60
  • 227 Ho CK, Wood JR, Stewart DR. , et al. Increased transcription and increased messenger ribonucleic acid (mRNA) stability contribute to increased GATA6 mRNA abundance in polycystic ovary syndrome theca cells. J Clin Endocrinol Metab 2005; 90 (12) 6596-6602
  • 228 McAllister JM, Modi B, Miller BA. , et al. Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. Proc Natl Acad Sci U S A 2014; 111 (15) E1519-E1527