Hyperandrogenism, PCOS and obesity after menopause : Meet the experts. Polycystic ovaries beyond menopause

Transcription

1 Hyperandrogenism, PCOS and obesity after menopause : Meet the experts Polycystic ovaries beyond menopause Serge Rozenberg CHU St Pierre Université libre de Bruxelles, Vrije Universiteit Brussel Belgium serge_rozenberg@stpierre-bru.be In the center of the city, in the center of life, with passion for care

2 Conflict of interest & Disclosure Conflicts of interest: nil Disclosure Research funding IRIS- King Baudouin Fondation, Vesale research Foundation, Amgen, MSD Speakers bureau &/or Advisory Boards Abbot, Pfizer, Will, Gedeon Richter, MSD, Amgen

3 Definition Polycystic Ovary Syndrome (MESH) A complex disorder characterized by infertility, HIRSUTISM; OBESITY; and various menstrual disturbances such as OLIGOMENORRHEA; AMENORRHEA; ANOVULATION. Polycystic ovary syndrome is usually associated with bilateral enlarged ovaries studded with atretic follicles, not with cysts. The term, polycystic ovary, is misleading. Year introduced: 1985 Hits : 11273

4

5

6

7

8

9

10 What happens after the menopause?

11 What are the risks related to PCOS in women after menopause? Cancer Endometrium Breast Ovary CVD Coronary Stroke DVT Metabolic Diabetes

12 Will the transition to menopause induce a normalisation or an additional insult?

13 The Stages of Reproductive Aging Workshop + 10 staging system for reproductive aging in women. Harlow et al Fertil Steril April; 97(4):

14 Fig. 1 A 20-Year Follow-up of Young Women With Polycystic Ovary Syndrome. Carmina, Enrico; Campagna, Anna; Lobo, Roger Obstetrics & Gynecology. 119(2, Part 1): , February DOI: /AOG.0b013e31823f7135 Fig. 1. Longitudinal changes of testosterone (ng/dl), body mass index (BMI), fasting insulin (microunits/ml), and waist circumference (cm) from the initial visit to the 20-year follow-up in 5-year intervals. Significant changes (PCarmina. Polycystic Ovary Syndrome After 20 Years. Obstet Gynecol At diagnosis, 57% had classic features (phenotype A), 9% had classic features without ovarian findings (phenotype B), 26% had the ovulatory phenotype (C), and 7% were nonhyperandrogenic (D). After 10 years, androgens decreased (P<.05); at 15 years, waist circumference increased (P<.05); at 20 years, ovarian volume decreased (P<.01). Serum luteinizing hormone and follicle-stimulating hormone decreased nonsignificantly and fasting insulin and quantitative insulin-sensitivity check index were unchanged. Eighty-five women (44%) were ovulatory at 20 years, and 18 women (8%) could no longer be diagnosed as having PCOS by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins, Inc. 2

15 PCOS into menopause The transition of women with PCOS into menopause and whether there is a specific phenotype for PCOS after menopause is poorly understood. There is evidence that women with PCOS have a larger cohort of primary follicles than age-matched control women before menopause. Serum T levels decrease as women age from the third to fifth decades. Additionally, women with PCOS often develop improved menstrual regularity with age. These factors may all contribute to improvement in reproductive functioning with age before menopause. Menopausal PCOS phenotype is poorly defined. The polycystic ovary criterion is likely not useful after menopause. Adapted from Consensus on women s health aspects of (PCOS): the Amsterdam ESHRE/ ASRM-Sponsored 3rd PCOS Fertil Steril 2012

16 PCOS & CANCER Is this condition associated with an increased risk of cancer? Endometrium Breast Ovary

17 Endometrial cancer

18 Factors known to alter the risk of developing endometrial carcinoma Increase Obesity, esp upper body Carbohydrate intolerance Nulliparity Late menopause PCOS Hypertension Unopposed oestrogen Functioning ovarian tumour Previous breast/colon cancer FH breast/colon/endom ca Tamoxifen Decrease Oral contraceptives Progestogens HRT cont combined Cigarette smoking Grand multiparity

19 Association between PCOS and endometrial cancer Systematic review of literature 14 studies comparative and non-comparative identified Meta analysis: OR for EC = 2.89 (95% CI; ) = 9% lifetime risk for Caucasian women with PCOS compared to 3% without PCOS Haoula Z, Salman M, Atioma W. Human Reproduction 2012 Feb 24 [Epub ahead of print]

20

21 Management of women with PCOS and amenorrhoea or oligomenorrhoea Conservative: Induction of artificial withdrawal bleeds Endometrial shedding at least every 3 months OR: Ultrasound measurement of endometrial thickness & morphology every 6-12 months ET >10mm warrants induction of bleeding, repeat scan +/- biopsy Balen A. Human Reproduction Update 2001; 7; 522-5

22

23 Forest plot of the associations between 5 kg/m2 BMI increase (linear model) and endometrial cancer risk by studies, which reported results stratified by hormonal replacement therapy (HRT) use. Crosbie E J et al. Cancer Epidemiol Biomarkers Prev 2010;19: by American Association for Cancer Research

24

25 PCOS AND BREAST CANCER RISK Obesity, hyperandrogenism and infertility are known risk factors for breast cancer Studies examining the relationship of PCOS to BC inconclusive with most not showing increased risk:

26 PCOS AND BREAST CANCER RISK 34,835 women aged from Iowa followed up (1.35%) reported history PCOS 883 incident breast cancers Benign breast disease RR 1.8 times after PCOS ( p <0.01) Breast cancer not more likely RR= 1.2 (95% CI ) Anderson KE et al. Cancer 1997; 79: 494-9

27 PCOS AND BREAST CANCER RISK UK follow-up 786 women with PCOS avg follow-up 30yrs; mortality compared with normal population: All neoplasms RR 0.91 (95%CI ) Breast cancer RR 1.48 (95%CI ) Pierpoint T et al. J Clin Epidemiol 1998; 51: 581-6

28 Adj. BC Standardized incidence rates in current users by type of HT & BMI (per 100 women aged years per year, never users as the standard Beral et al 2011

29

30 J.M. Schildkraut, et al Epithelial ovarian cancer risk among women with polycystic ovary syndrome Obstet Gynecol, 88 (1996), pp

31

32 PCOS AND RISK OF OVARIAN CANCER? Ovulation induction Polycystic ovary is hypersensitive to stimulation Few small studies Largest study from UK: Follow-up 786 women with PCOS ; avg follow-up 30yrs; mortality compared with normal population: All neoplasms RR 0.91 (95% CI ) Ovarian cancer RR 0.39 (95% CI ) Pierpoint T et al. J Clin Epidemiol 1998; 51: 581-6

33 Proteomic biomarkers for ovarian cancer risk in women with polycystic ovary syndrome: a systematic review and biomarker database integration A panel of six biomarkers was overexpressed both in women with OC and in women with PCOS. These biomarkers include calreticulin, fibrinogen-γ, superoxide dismutase, vimentin, malate dehydrogenase, and lamin B2. Galazis et al Fertil Steril Dec;98(6):

34 Guidelines As there does not appear to be an association with breast or ovarian cancer, no additional surveillance is required beyond routine screening. Green-top Guideline No 33. Long-term consequences of Polycystic Ovary Syndrome Royal College of Obstetricians and Gynaecologists

35

36 In total, about 45 50% of young women with PCOS have increased atherogenic risk determined by altered classic or non-classic lipids. Cardiovascular risk and events in polycystic ovary syndrome. Carmina E. Climacteric. 2009;12 Suppl 1:22-5. Review

37 PCOS & coronary heart disease At an early age, insulin resistance dyslipidemia (CHD) increased central adiposity. It can be hypothesized that the menopausal transition, whether natural or surgical, may provide an additional insult, resulting in greater cumulative risk to their vasculature.

38 Atherosclerosis 1 1. Ross. N Engl J Med 1999; 340:

39 Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Coronary artery calcification (CAC)= measure of subclinical atherosclerosis (SCA) 149 PCOS cases and 166 controls (mean age 47.3 and 49.4 respectively). Talbott et al Vasc Health Risk Manag. 2008;4(2):

40 Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Cases had a higher prevalence of CAC (63.1%) vs controls (41.0%), (p = 0.037) after adj. for age and BMI. There was a significant difference in CAC values between cases and controls irrespective of menopausal status and type. Talbott et al Vasc Health Risk Manag. 2008;4(2):

41 Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Talbott et al Vasc Health Risk Manag. 2008;4(2):

42 Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Talbott et al Vasc Health Risk Manag. 2008;4(2):

43 Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Logistic regression was carried out with CAC (> 10 vs < 10) as the dependent variable, and independent variables: PCOS status, current age, BMI, and menopausal status, and selected CHD risk factors. PCOS status and fasting glucose were significant risk factors for CAC (p 0.05). Both natural and surgical menopause were independent risk factors for CAC as well (p 0.01). Talbott et al Vasc Health Risk Manag. 2008;4(2):

44 PCO & CVD Initial studies estimated that postmenopausal women with previous PCOS have a 7.1 higher risk than non-pcos women of developing myocardial infarction. Dahlgren E, et al. Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 1992; 71:

45 PCO & CVD Review of death certificates of 786 women (UK) diagnosed with PCOS 26.4 years average followed up No statistically increase in cardiovascular mortality This study has been criticized diagnosis of PCOS based on historical data not supported by hormonal studies or ovarian morphology. In a later report, the same authors noted a higher prevalence of cerebrovascular accidents in women who had PCOS during their fertile age. Pierpoint T, Mortality of woman with polycystic ovary syndrome at long term follow up. J ClinEpidemiol 1998;51:581 6 Wild SH, Pierpoint T, Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol 2000;52:

46 Nurses Health Study, Followed women for 14 years: Very irregular menses RR : 1.5 (95% CI ) for CHD RR : 1.9 (95% CI ) for fatal MI compared with eumenorrheic women Dawber et al Epidemiological approaches to heart disease: the Framingham Study. Am J Public Health 1951;41:279 81

47 Women s Ischemia Evaluation Study (WISE): 104 postmenopausal women with PCOS and a control group of 286 matched normal postmenopausal followed prospectively for close to 10 years; multi-vessel cardiovascular disease was observed in 32% of PCOS women compared to 25% of non- PCOS women (OR 1.7) Shaw LJ, 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 NIH, NHLBI (WISE). JCEM 2008

48 PCO & mortality Retrospective data in women with polycystic ovaries suggest mortality occurs at a similar rate as in the general population and presumably at the same age. Alternative data suggest they have higher rates of stroke and CVD. Adapted from Consensus on women s health aspects of (PCOS): the Amsterdam ESHRE/ ASRM-Sponsored 3rd PCOS Fertil Steril 2012

49 Manson Oct 2013

50 Stroke rates attributed to HRT, according to patient age 1 Analyses applied the relative risk of 1.4 for hormone therapy and stroke observed in the overall cohort in the study to the stroke rates for each age group. 1. Adapted from Grodstein F, et al Arch Intern Med. 2008;168(8):

51 Manson Oct 2013

52 Manson et al JAMA Oct 2013

53 Conclusions In some patients, the consequences of PCO may decrease with menopausal transition Still women with PCOS have a 2.7-fold (95% CI, ) increased risk for endometrial cancer. Combined continuous MHT may reduce this risk but not annihilate it. There is doubt about whether PCO affected women are at increased risk for breast and ovarian cancer.

54 Conclusions The long-term risk for morbidity and mortality among postmenopausal women with a history of PCOS may be increased due to CVD Lifestyle changes should be advocated Risk factors should be corrected MHT need to be prescribed on an individual base evaluating benefits and risks. Genomewide association studies will may be identify new genes/pathways involved in ovarian dysfunction related to age of menopause and polycystic ovaries.

55

56 Manson Oct 2013