Disclosures. Natural history 23/05/2018. Conflicts of interests: nil. PCOS: Developmental origin

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1 Disclosures PCOS intervention: On the continous clinical challenge! Sven O. Skouby, MD, DMSc Conflicts of interests: nil Reproductive Medicine Unit Dep. Ob/Gyn. Herlev/Gentofte Hospital, Faculty of Medical and Health Sciences University of Copenhagen, Denmark Learning objectives Learning objectives Prevalence of PCOS: >10% The most prevalent endocrine dysfunction among fertile women Etiology: unknown Apart from ovarian dysfunction clinical penetration of metabolic disturbancies and CVD risk are linked to PCOS phenotypes Intervention therapy may depend on pregnancy wish or solely metabolic or cosmetic problems Often it is a mixture of this triade 3 4 PCOS: Developmental origin Genetic predisposition (Insulin resistance) Prenatal exposure to androgen? Natural history Central obesity Abnormal LH secretion High LH Insulin resistance Hyperandrogenism Anovulation sos/pcos/2012 1

2 23/05/2018 Consensus on women s health aspects of polycystic ovary syndrome (PCOS): the Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group PCOS PCO: Life-time expression a conditioning requiring life long attention? Tekst starter uden Pubertas precox Hirsutism Obesity Irregular bleedings Anovulation Infertility Type-2 DM CVD Cancer 60 yrs 15 yrs Sted og Low birthweight Metabolic disease Reproductive disorders Future health child Future health women Birth Puberty Adolescense Fertile period Senescense Fertility and Sterility, Volume 97, Issue 1, 2012, e25 Enhedens PCOS: Phenotypes are dependent on genetics, epigenitics and enviroment PCOS Tekst starter uden Patophysiology Ovarian dysfunction Sted og 12 Enhedens Rotterdam consensus: Definition of PCOS Hormonal interactions in PCOS Tekst starter uden The Rotterdam criteria 1. Oligo-/amenorrhoea 2. Clinical and/or biochemical hyperandrogenism 3. Polycystic ovaries (PCO) And exclusion of other related disorders Sted og 17 Enhedens Fauser B.C.et el, Hum Repod 2004 Jan;19(1):41-7 2

3 Herlev /Gentofte Ho PCOS phenotypes according to the Rotterdam criteria PCOS and BMI Features Phenotype 1 Phenotype 2 Phenotype 3 Oligo-/amenorrhoea Clinical and/or biochemical hyperandrogenemia Heterogeneity! Phenotype % BMI > 30 Polycystic ovaries PCOS phenotypes translate to different endocrine and metabolic consequences PCOS: Consequenses of IR - However, for most benefical intervention attempts increase in insulin sensitivity seems to be pivotal PCOS: Consequenses of IR 3

4 Herlev Hospital PCOS: CVD in relation to phenotypes Are phenotypes of women with PCOS based on BMI and insulin resistance are more causally associated with distinct CVD risk profiles BMI PCOS: CVD in relation to phenotypes In flammation and thrombosis: ETP and CRP low CRP, Low ETP 70 High CRP, High ETP IR +Obesity +IR +Obesity IR 20 IR Obesity +IR Obesity 10 0 BMI 25-IR BMI 25+IR BMI>25-IR BMI>25+IR The selection of studies included (n=104392) May 22, 2016 Meta-analysis of the association between PCOS and CVD CHD; OR:1.44 P=0,04 MI; OR:1.01 P=0.95 Ovulation disorder PCOS: Treatment 4

5 PCOS Clinical question: Use of OCs in PCOS? Increased thrombosis risk or metabolic benefits? -but no actual pregnancy wish Effect of a new oral contraceptive with estradiol valerate/dienogest on carbohydrate metabolism OC s vs metformin Metformin versus oral contraceptive pill in polycystic ovary syndrome: a Cochrane review Michael F. Costello 1,2,3,6, Bhushan Shrestha 1, John Eden 1, Neil P. Johnson 4 and Peter Sjoblom 5 Change in HOMA-IR values at baseline and 3 months after E2V/DNG treatment. Boxes represent value distribution; vertical lines represent on the bottom the minimum value and on the top the maximum value. Data are presented as medians and IOR. ***p<.001. Vincenzo De Leo, Franca Fruzzetti, Maria Concetta Musacchio, Valeria Scolaro, Alessandra Di Sabatino, Giuseppe Morgante 1 Division of Obstetrics and Gynaecology, School of Women's and Children's Health, University of New South Wales, Royal Hospital for Women, Sydney, NSW, 2031, Australia 2 Department of Reproductive Medicine, Royal Hospital for Women, Sydney, NSW, Australia 3 IVFAustralia, Sydney, NSW, Australia 4 National Women's The Department RCT evidence of Obstetrics and to Gynaecology, date does University of Auckland, Auckland, New Zealand 5 Fertility Centre Scandinavia, Stockholm not show adverse metabolic risk with the use of the OCs compared with metformin Storangsvagen 10, Stockholm, Sweden Human Reproduction : Contraception, Volume 88, Issue 3, 2013,

6 OC s + metformin The available data do not offer enough evidence to advocate the standard use of combined treatment in PCOS Basis of newer drug combinations with OCs? The discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin s mechanisms which benefit reproductive physiology 6

7 Glucagonlike peptide-1 (GLP-1) Int J Endocrinol. 2016; 2016: Published online 2016 Oct 23. doi: /2016/ PMCID: PMC PMID: Meal Increases transit time Body weight Effects of Inositol(s) in Women with PCOS: A Systematic Review of Randomized Controlled Trials Vittorio Unfer, John E. Nestler, Zdravko A. Kamenov, Nikos Prapas, and Fabio Facchinetti 1, * 5 1 Department of Medical Sciences, IPUS-Institute of Higher Education, Chiasso, Switzerland 2 Department of Medicine and Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA 3 Clinic of Endocrinology, Alexandrovska University Hospital, Medical University, Sofia, Bulgaria 4 IAKENTRO, Infertility Treatment Center, Thessaloniki, Greece 5 Mother-Infant Department, University of Modena and Reggio Emilia, Modena, Italy *Vittorio Unfer: vunfer@gmail.com Academic Editor: Michael Horowitz Received 2016 Jul 6; Accepted 2016 Sep 22. Blod glucose Decreased Mæthed hunger 47 Herlev og Gentofte Hospital GLP-1 intervention Research M Nylander et al. Liraglutide in PCOS: in effects PCOS: on pro-thrombosis effects on pro-thrombosis : :89 Open Access GLP-1, liraglutide (Victoza ) Liraglutide in polycystic ovary syndrome: a randomized trial, investigating effects on thrombogenic potential Malin Nylander 1,2, Signe Frøssing 2,3, Caroline Kistorp 2,3, Jens Faber 2,3 and Sven O Skouby 1,2 1 Department of Obstetrics and Gynecology, Herlev Gentofte Hospital, Herlev, Denmark 2 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 3 Department of Internal Medicine, Endocrine Unit, Herlev Gentofte Hospital, Herlev, Denmark Correspondence should be addressed to M Nylander machny@dadlnet.dk 5/23/18 48 Liraglutide and PCOS Intervention with GLP-1 analog in overweight PCOS women Improved bleeding pattern, Increased SHBG CONCLUSION Decreased deposition of perihepatic fat mass No effects on markers of endothelial dysfunction or low-grade inflammation Conclusion: PCOS intervention Promising basis for use of new drugs: Yes -combined with OCs? Jury is still out! 7

8 THANK YOU! 8