Polycystic ovarian syndrome Dr. Nizar Albache Head of Diabetes Research Unit, Aleppo University President of Syrian Endocrine Society July 25 2011 Key Learning Objectives To be able to recognize and diagnose PCOS To understand the lifelong manifestations of PCOS To understand management options for: longterm health hirsutism infertility Prevalence & Diagnosis PCOS - past and present Stein-Leventhal Synd. Menstrual disorder Hirsutism Obesity Infertility PCO Stein IF, Leventhal ML. Am J Obstet Gynecol. 1935;29:181-191. The celebrated “La Barduba” by Ribera, a 52-year-old lady nursing her child. She became markedly hirsute at age 37 after having had spontaneous abortions. three FREQUENCY OF PCOS •General population •Women with secondary amenorrhea • women with oligomenorrhea •Women with hirsutism •Normal women met the sonographic criteria for pcos •Anovulation in women diagnosed with pcos 75% •Anovulation in hirsute women with normal menses 4% - 8% 30% 75% 90% 23% 40% How to make a diagnosis Clinical suspicion Primary or secondary amenorrhoea Oligomenorrhoea Unexplained infertility Acne/ hirsutism Obesity HIRSUTISM : excessive growth of body hair in women at androgen-dependent areas: very few hairs are found - LIPS - CHIN - CHET - ABDOMEN - BACK - FEMORAL REGION where normally HIRSUTISM CLASSIFICATION From Slight Hirsutism To Virilim Ferriman-Gallwey score : 9 areas Score = 0 – 4 N=6–8 HIRSUT >8 VIRILISM 36 VERY SUBJECTIVE 18% OVERLAP REPORTERS DIFFERENCES NO FLEXIBILITY Change in the form and rate of hair growth * Recently: a technique for assessing Hirsutism : video equipment and computer software. Digital imaging of hair development Criteria For The Diagnosis Of Polycystic Ovary Syndrome (Pcos) NIH (1990) TO INCLUDE ALL OF THE FOLLOWING: 1: HYPERANDROGENISM AND/OR HYPERANDROGENAEMIA 2: OLIGO-OVULATION 3: EXCLUSION OF RELATED DISORDERS ESHRE/ARMS (ROTTERDAM TO INCLUDE TWO OF THE FOLLOWING, INCLUDING THE EXCLUSION OF 2003) RELATED DISORDERS: 1: OLIGO- OR ANOVULATION 2: CLINICAL AND/OR BIOCHEMICAL SIGNS OF HYPERANDROGENISM 3: POLYCYSTIC OVARIES ANDROGEN EXCESS SOCIETY (2006) TO INCLUDE ALL OF THE FOLLOWING: 1: HIRSUTISM AND/OR HYPERANDROGENAEMIA 2: OLIGO-ANOVULATION AND/OR POLYCYSTIC OVARIES 3: EXCLUSION OF ANDROGEN EXCESS OR RELATED DISORDERS PCOS definition Chronic Anovulation and Hyperandrogenism 5-10% reproductive age women Diagnosis: 2/3 criteria * 1. Oligo-ovulation &/or anovulation 2. Hyperandrogenism (clinical or biochemical) 3. Polycystic ovaries on ultrasound (PCO) * other causes for hyperandrogenism excluded ESHRE/ASRM PCOS Consensus Workshop May 2003 Diagnosis: PCO on ultrasound At least 1 ovary with 12+ follicles 2-9mm &/or ovarian volume > 10mls NB: US picture on 1 occasion suffices for diagnosis 25% of women have PCO, but only 5% have PCOS ESHRE/ASRM PCOS Consensus Workshop May 2003 Differential diagnosis of PCOS: The differential diagnosis of hirsutism & oligomenorrha includes: - congenital adrenal hyperplasia - cushing syndrome - hyperthecosis ovarii - benign & malignant androgen secreting tumors or ovaries. Causes & Mechanisms Pathophysiology of PCOS: PCOS is a condition that originates possibly at the time of puberty due to interplay of: (1) obesity & excess of ovarian androgen production, due to hyperinsulinemia (2) intrauterine environment. (3) genetic factors both X-linked, autosomal dominant modes of inheritance. (4) disturbance to hypothalamic-pituitary-ovarian axis. Causes Syndrome = a collection of symptoms and signs. There is no single cause but multiple predisposing factors. Genetic Family linkage studies Over 70 candidate genes investigated Steroidogenic & insulin pathways, ovarian follicle development Candidate genes may regulate hypothalamic-pituitaryovarian axis, as well as those resposible for insulin resistance Environmental Fetal programming/ ‘thrifty gene hypothesis’ Obesity Insulin Resistance Insulin resistance (IR): is a prominent feature in both obese (65-90%) and lean (25-45%) women with PCOS is unique to PCOS as occurs independently to obesity, but is aggravated by obesity (Franks S 1989; Dunaif A 1994) Weight increase SHBG decreases Inherited defects in insulin actions Insulin increase Insulin receptor disorders Theca (IGF-II, ?IGF-I) IGFBP-1 decrease By direct inhibition of hepatic synthesis of SHBG & IGFBP -1 Intrauterine Environment & PCOS: Hague et al 1988 postulated that the intrauterine environment has a role in the pathogenesis of PCOS, & suggested that hyperandrogenism during fetal life may be the determining factor. The apparent influence of intrauterine milieu in poorly controlled diabetics who end with stillborn fetuses, showed ovarian changes similar to those seen in PCOS. Compensatory Hyperinsulinemia Insulin resistance ? Androgens Ovary Cause-and-effect relationship Serum insulin Pathophysiology Insulin acts synergistically with lh to enhance androgen production in the ovarian theca cells Insulin also decreases hepatic synthesis and secretion of sex hormone-binding globulin Women with pcos and hyperinsulinemia typically have elevated free testosterone but the total testosterone concentration may be at the upper range of normal or only modestly elevated PCOD Obese Non-obese GH LH Different hormone concentrations in obese and non-obese PCO patients LH and IGF-I effect on theca cells Insulin resistance Hyperinsulinemia IGFBP-I IGF-I Cytochrome p-450c 17-alpha activity Androgen secretion SHBG Insulin resistant and non-resistant PCOS 18 37 patients 19 Insulin resistant Non-insulin resistant Weight/height 2 P<0.0001 40 P<0.02 P<0.017 40 P<0.0001 20 P=NS 20 P<0.027 BMI Meirow et al. Hum Reprod 1995 LH Andr Test SHBG Estrad Role of leptin in the pathophysiology of PCOS: Leptin is considered as one of the major peripheral signals that affects food intake & energy balance. Obesity is a classic condition of circulating leptin excess. Leptin (OB) 16 KDa protein encoded by ob gene. Expressed & secreted by – adipocytes, placenta, gastric epithelium. Directly proportional to the total amount of fat in the body. mice are homozygous for single gene mutation. ob/ob –protein hormone leptin db/db –receptor for leptin . High degree of homology Role of leptin in the pathophysiology of PCOS: The discrepancy between increased leptin blood levels & its central effects represents a leptin resistance as shown by study of Moschos et al 2002 in Fertility Sterility Journal. Mitchell m in 2005, there is evidence that leptin acts directly on the ovaries through functional receptors defect. Role of leptin in reproduction Fertility influenced by stored body fat Leptin signals the onset of puberty . Regulates hypothalamic- pituitary – ovarian function . Signalling Pathway of Leptin Action Potential Role Of The Endocannabinoid System involved in the dynamic & homeostatic regulation of feeding & energy metabolism. regulate multiple endocrine functions including H-P-O axis fluctuates during ovarian cycle in both the hypothalamus & pituitary, thus influencing hormonal secretion & sexual behavior through CB1 receptor activation Despite JP et al 2005 used rimonabant in patients as a new pharmacological treatment for tackling obesity Table :Representative Candidate Genes with Evidence of Linkage, Association, or Both, with the Polycystic Ovary Syndrome (PCOS) Pathway and protein (Gene) Insulin secretion and action Insulin receptor (INSR) region-D195884 Insulin variable-number tandem repeats (VNTR) Insulin receptor substrate 1 (IRS-1) Insulin receptor substrate 2 (IRS-2) Calpaim 10 (CAPN10) Peroxisome-proliferator-activated receptor g (PPAR g) Protein phosphatase 1 regulatory subunit (PPP1R3) Gonadotropin secretion and action Follistatin (FST) Androgen biosynthesis, secretion, transport, and metabolism Androgen receptor (AR) Sex hormone-binding globulin (SHBG) Cytochrome P450c17 (CYP17) Cytochrome P-45011a (CYP11a) 11b-hydroxysteroid dehydrogenase (11b-HSD) and hexose-6-phosphate dehydrogenase (H6PD) life-long condition PCOS is a life-long condition Cancer (uterine; ?breast) Hirsutism Menstrual irregularities Hypercholesterolaemia Diabetes Hypertension ? Pronounced adrenarche Infertility, miscarriage Gestational hypertension Gestational diabetes ? IUGR 0 Longterm health 10 20 Precocious puberty 30 40 Reproductive disorder 50 Coronary heart disease 60 70 Age (years) Metabolic syndrome PCOS and glucose intolerance Increased prevalence of glucose intolerance (35%) and type 2 diabetes (10%) Also increased in non-obese PCOS (10%, 1.5%) Increased risk (x3-7) of developing type 2 diabetes PCOS women develop glucose intolerance at an early age (3rd-4th decade) PCO is risk factor for gestational diabetes Long-term health risks Established: Reproductive: Endometrial Cancer Metabolic: Diabetes, Dyslipidaemias, Hypertension, Obesity Unproven: Cardiovascular Disease Breast cancer Acanthosis Nigricans ( An ) Is A Clinical Marker Of Ir “Velvety, mossy, verrucous, hyperpigmented skin change often found over the nape of the neck, in the axillae or beneath the breasts Caused from the binding of insulin to insulin-like growth factor receptors on keratinocytes and fibroblasts which results in hyperplasia of the skin IR is present in more than 90% of patients with AN Evaluation The 3 steps of androgen metabolism in women Adapted from: Beylot C. et al. Oral Contraceptives and Cyproterone Acetate in Female Acne Treatment. Dermatology 1998; 196: 148-152. Investigations Serum (early follicular phase): LH/FSH Total testosterone, Free androgen index (FAI) Exclude other endocrinopathies *TSH, Prolactin, DHEAS, 17-OH progesterone Pelvic ultrasound scan for the ovarian features of PCO Diabetes screen, lipid profile , BP check Hormone levels: PCOS vs. Idiopathic hirsutism Baseline plasma hormone levels in patients with PCOS or idiopathic hirsutism and in healthy women (mean values) Hormone PCOS n=213 LH (IU/L) FSH (IU/L) Androstenedione (µg/L) Testosterone (T) (µg/L) Free T (ng/L) DHEAS (mg/L) 3a-diolG (µg/L) SHBG (nmol/L) 14.3* 5.3 3.6* 1.0* 3.6* 2.9* 6.3** 22.1* Idiopathic hirsutism n=97 Healthy women n=40 3.5 5.5 2.0 0.5 1.8 1.9 6.0** 49.8 3.7 5.8 1.8 0.4 1.6 1.6 1.5 51.1 *=p<0.001: PCOS vs. idiopathic hirsutism and healthy women **=p<0.001: PCOS and idiopathic hirsutism vs. healthy women Falsetti L. et al. Management of Hirsutism. Am J Clin Dermatol 2000 Mar-Apr; 1 (2): 89-99 Metabolic problems Hypertension Dyslipidaemia TC, LDL-C, TG’s HDL-C Future diabetes ? Cardiovascular disease (CVD) coronary disease myocardial infarction Figure Diagnostic alogorithm for the Polycystic Ovary Syndrome Any 2 of the following 3 disorders confirmed: Oligomenorrhea or amenorrhea Hyperandrogenism (e.g., hirsutism, Acne, alopecia) or hyperandrogenemia (e.g., elevated levels of total or free Testosterone) Polycystic ovaries on ultrasonography All of the following disorders ruled out: Hyperprolactinemia Nonclassic congenital adrenal hyp[erplasia Cushing’s syndrome Androgen –secreting neoplasm Acromegaly Polycystic ovary syndrome Ancillary studies Risk assessment for Endometrial carcinoma Endometrial biopsy If risk increased Risk assessment for Glucose intolerance Oral glucose-tolerance test If risk increased Fasting chol, HDL Chol, Tg, LDL-c Risk assessment for obstructive sleep apnea Polysomnography If risk increased Treatment Management of PCOs Primary or secondary amenorrhoea Oligomenorrhoea Acne/ hirsutism Obesity infertility Long-term health risk Treatment: The first step is to help the patient understand that this chronic disease process can be controlled by changes in lifestyle. Lifestyle modification must be emphasized to include appropriate diets & exercise program is essential. Treatment (cont): Metformin may complement the effects of lifestyle modification, it causes marked improvement in menstrual pattern & may improve the response to ovulatory agents. Clomifene-citrate is the standard first line method of medical ovulation induction in anovulatory women. The second line treatment, laparoscopic ovarian diathermy, gonadotrophin therapy. Treatment (cont): Adrenal suppression by dexamethasone 0.5mg at night facilitate ovulation. Anti-androgens: cyproterone acetate & EE in combination (dianatte) Spironolactone: alternative anti-androgen. Low dose of oral contraceptives are effective in treating acne & hirsutism, minimum of 2 years & cosmetic measures are needed to achieve good results. Lifestyle/Diet Caloric reduction Estimated caloric deficit of 3500 kcal =0.45 kg of fat Reducing intake &/or increasing expenditure Usual target is dietary reduction of 500 kcal/day to achieve a deficit of 3500 kcal/week (15% protein, 30% fat) What is a healthy diet? Less 20-30 % of total K Carbohydrate: 55% Protein: 15% Fat: 30% Variety Moderation Pharmacologic therapy for pcos AGENT MECHANISM OF ACTION USES EXAMPLES ANTIANDROGENS INHIBIT ANDROGENS FROM BINDING TO THE RECEPTORS ANDROGEN SYMPTOMS (E.G., HIRSUTISM, ACNE, OILY SKIN SPIRONOLACTONE (ALDACTONE): 50200 MG/DAY FLUTAMIDE (EULEXIN): 250 MG BID OR TID BIGUANIDES REDUCES HEPATIC GLUCOSE PRODUCTION, LOWERING INSULIN LEVELS; POSSIBLE IMPROVEMENT IN OVARIAN STEROIDOGENESIS ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY; OVULATION INDUCTION; INSULIN RESISTANCE METFORMIN (GLUCOPHAGE): INITIALLY, 500 MG BID OR 850 INCREASE FROM 500 MG TWICE DAILY TO 850 MG TWICE DAILY MAXIMUM DAILY DOSE IS 2.5 G IN TWO OR THREE DIVIDED DOSES CLOMIPHENE CITRATE (CLOMID ANTIESTROGEN; ACTS TO INDUCE RISE IN FSH AND LH OVULATION INDUCTION CLOMID: START WITH LOWEST AVAILABLE DOSE (50 MG), WITH 50 MG INCREMENTS OF INCREASED DOSAGE IF OVULATION IS NOT DETECTED HORMONAL CONTRACEPTION (ESTROGEN-PROGESTIN COMBINATION THERAPY) INCREASES SHBG; SUPPRESSES LH AND FSH; ANTIANDROGEN ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY ORAL CONTRACEPTIVES; ORTHO EVRA TRANSDERMAL PATCH; NUVARING THIAZOLIDINEDIONE ENHANCES INSULIN ACTION AT TARGET TISSUES LEVEL ANDROGEN SYMPTOMS; MENSTRUAL IRREGULARITY; OVULATION INDUCTION; INSULIN RESISTANCE PIOGLITAZONE (ACTOS): INITIALLY 15 MG OR 30 MG ONCE DOSAGE 45 MG ONCE DAILY Metformin Women with PCOS: over 6 years: 9% develop impaired glucose tolerance 8% develop diabetes Metformin can reduce progression to diabetes by 31% in non-PCOS populations Metformin Direct intracellular effects to reduce hepatic gluconeogenesis, improve glucose metabolism Target dose: 1500 – 2550mg daily with meals Most common side effects are GI (diarrhea, nausea/vomiting, flatulence, indigestion, abdo discomfort) Rare problem of lactic acidosis: never been reported in PCOS Metformin in PCOS • ‘Lifestyle’ 1st line treatment if overweight • Some advocate lifelong metformin from puberty • Currently no long-term data on metformin use • Uncertain advantage adding metformin to OCP Effect of Metformin on Lean PCOS 140 Improvement in: • menstrual pattern • fertility +/- clomid Before 120 After 100 80 60 40 20 0 Fast. Insulin pmol/L Free T pmol/L SHBG nmol/L Nestler, JCEM, 1997 Glitazones: potential Impact on CVD Risk Hyperglycemia BP HDL and sdLDL PAI-1 TZD IR CRP Microalbuminuria Vascular reactivity Atherosclerosis, CVD? OCP use in PCOS women Outcome Improvement No effect Worsening Glucose tolerance Pasquali 1999 Korythowski 1995 Morin-Papunen 2003a & b Cagnacci 2003 Guido 2004 Nader 1997 Morin-Papunen 2000 Insulin resistance & sensitivity Pasquali 1999 Morin-Papunen 2003b Armstrong 2001 Cibula 2002 Guido 2004 Korythowski 1995 Dahlgren 1998 Vrbikova 2004 Mastorakos 2006 Lipid levels Falsetti 1995 Mastorakos 2002 Guido 2004 Pasquali 1999 Prelevic 1990 Mastorakos 2002 Guido 2004 Pasquali 1999 Prelevic 1990 Falsetti 1995 Mastorakos 2002 Guido 2004 Vrbikova 2005 The pill is safe in PCOS women Diane-35 in acne: antiandrogenic effect on the target tissue Acne is the most common skin disease – affecting 80% of females at some time after the onset of puberty Most patients seem to have sebaceous glands that are hypersensitive to androgens Leyden J. Therapy for acne vulgaris. N Engl J Med 1997; 336: 1156-1162 Treatment: 2-menstrual irregularity Oral contraceptives have clear benefits : 1) Induction of regular withdrawal bleeding 2) Protection of the endometrium from unopposed estrogen 3) Reduction in LH secretion and consequent reduction in ovarian androgen secretion 4) Increased levels of sex hormone-binding globulin and a consequent reduction in free testosterone 5) Improvement in hirsutism and acne CPA 2 mg / EE 35 µg in PCOS: Hormone levels after 9 cycles treatment (n = 46) LH/FSH ratio: p<0.001 Testosterone: p<0.001 Androstenedione: p<0.025 DHEAS: p<0.02 SHBG: p<0.0001 Prelevic et al. Gynecol Endocrinol 1989; 3: 269-280 Reverse-Sequential Treatment Androcur 10 Drospirenone An analogue of spironolactone it has : • An antiandrogenic activity • Less or non antimineralocorticoid • Approved for use in combination with E.E For PCOS and hirsutism Drospirenone is different • Drospirenone is a novel class progestogen • Drospirenone is derived from 17α-spirolactone • Drospirenone’s pharmacological profile is closer to natural progesterone than any other currently available synthetic progestogene A normal cycle ( no oral contraceptive) Estrogen Day1-14 Salt/Water Retention Renin-angiotensinaldosterone system (RAAS) Angiotensin I + Estrogen Renin substrate (angiotensinogen) Natural Prog will Counter balance Estrogen mediated fluid/water retention Na+/water retention K+ elimination Progesterone Aldosterone Angiotensin II Renin-angiotensin-aldosterone system (RAAS) Angiotensin I + Estrogen Renin substrate (angiotensinogen) Less Water retention-related symptoms (edema, bloating, weight gain) Na+/water retention K+ elimination Progesterone DRSP Aldosterone Angiotensin II Mean change in body weight while using Yasmin and EE/DSG 1 0.8 Yasmin (n = 450) EE/DSG (n = 450) 0.6 Difference in kg 0.4 0.2 0 –0.2 –0 .4 –0.6 –0.8 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 p < 0.0001 Cycle p < 0.0009 Follow up 26 The pill versus metformin OCP Cycle control Contraceptive Side effects Contraindications Reduce ovarian cancer Metformin Induce ovulation 70% No contraception Well tolerated No contraindications Only use if proven hyperinsulinaemia ?? Infertility: anovulatory Weight loss if BMI >25 (diet/ exercise) Clomid (50 - 150mg) versus metformin Clomid and metformin combined FSH stimulation Ovarian drilling IVF IVM Clomiphene citrate Used since 1960s Safe to use for 9-12 months continuously Oestrogen receptor antagonist: boost natural FSH release Can have detrimental effect on endometrium Try tamoxifen alternative FSH stimulation Low doses Need cycle monitoring Pregnancy rates 15-20% Ovarian drilling As effective as FSH stimulation ‘natural conception’ No multiples Laparoscopy Risk of adhesions (unproven) Free Androgen Index and the outcome of LOD % * P < 0.05 ** P < 0.01 *** P < 0.001 100 80 60 *** 40 ** 20 0 <4 4-14.9 Ovulation >14.9 Pregnancy FAI BMI and the outcome of LOD % * P < 0.05 ** P < 0.01 *** P < 0.001 100 80 60 ** 40 * 20 0 <29 29-34 Ovulation >34 Pregnancy BMI (kg/m2) Randomized controlled trial comparing laparoscopic ovarian diathermy with clomiphene citrate as a first-line method of ovulation induction in women with polycystic ovary syndrome Amer, Li, Metwally, Emarh & Ledger Human Reproduction 2009 Ovulation LOD group (n=33) 64% Clomiphene group (n=32) 76% Conception after first 27% treatment Conception after second 53% treatment ( at 12m) miscarriage 12% 44% Live Birth 56% 46% 63% 10% SUMMARY Laparoscopic ovarian diathermy, a very simple form of surgery, has a high success rate and has a definite, useful role in the management of anovulatory infertility in women with PCOS. With Proper Patient Selection, The Pregnancy Rate After Laparoscopic Ovarian Diathermy Is Up To 80 % IVF Best way to achieve singlet on pregnancy in PCOS infertility Main risk is OHSS (ovarian hyperstimulation syndrome) Low doses of stimulation Careful and frequent monitoring Co-treatment with metformin unproven benefit: ongoing trial at IVFA Blastocyst transfer Sometimes freeze all embryos IVM (in vitro maturation) Collect immature eggs Culture in vitro Fertilise and transfer embryos Few centres worldwide Recently reported 1st success in UK Twins as 2 embryos transferred 400 babies born (versus >2 million IVF) Pregnancy Outcomes: Maternal: Gestational Diabetes (OR 2.94) Pregnancy induced hypertension (OR 3.67) Cesarean sections Acne Neonatal: Admission to ICU Premature delivery (OR 1.75) metformin during pregnancy ? Management of PCOS-longer term consider OCP, metformin, progestins, antiandrogens, ovulation induction, lipid lowering agents, antihypertensives as necessary surveillance for diabetes, hypertension and dyslipidemia especially if positive family history and overweight monitor endometrium active weight loss and exercise programme Conclusions 1. PCOS is common. 2. Always focus on presenting problem, but also educate patients about the long-term health risk 3. Life-style modification is a very effective treatment option in PCOS. 4. Do not be scared of using the OCP. 5. Drospirenone has more advantages than others OCP The presence of polycystic ovaries and/or PCOS Cannot be elicited by a cursory evaluation alone Only 50% of women with PCOS are overweight THANK YOU