PCOS: A Different Look at an Old Disease. Dr. Adi E. Mehta, MD. Staff, Endocrine & Metabolism Institute, Cleveland Clinic.

Transcription

1 PCOS: A Different Look at an Old Disease Dr. Adi E. Mehta, MD. Staff, Endocrine & Metabolism Institute, Cleveland Clinic.

2 Diagnostic Criteria for PCOS It is noteworthy that all reviews of and guidelines for diagnosis and management of PCOS note the association of the disorder with long term risk for gestational diabetes, the Metabolic Syndrome, Type 2 diabetes and cardiovascular disease

3 Polycystic ovary syndrome (PCOS) pathogenesis Insulin resistance: - postreceptor defect in tyrosine kinase activity - dysfunction of GLUT-4 - defect of the insulin receptor - anti-receptor antibodies Compensatory hyperinsulinemia Decrease in SHBG and IGFBP-1 production Excessive androgen production

4 SO, WHAT IS THE CONNECTION BETWEEN THE REPRODUCTIVE AND METABOLIC ASPECTS OF THE SYNDROME?

5 Partitioning of metabolic fuels by priority

6 Nutrition, Weight & Reproductive Function Nutrition and reproduction are intimately connected Weight is an important trigger for puberty Weight and nutrition affect fecundity obesity is an independent risk factor for anovulation Extreme leanness, independent of anorexia, causes amenorrhea Malabsorbtive GI disease is associated with subfecundity

7 Variability of the PCOS Phenotype PCOS women can be divided into 2 phenotypes: 4 of 5 are overweight, hirsuit, & have a high ovarian secretion of androgens These women were born with above average birthweight 1 of 5 are normal weight They were born to overweight mothers usually with prolonged gestation Characterized by an altered hypothalamic control of LH secretion

8 Weight, Diet & Menstrual Cycles Sibling studies have revealed that in hyperandrogenic women, weight determines cycle regularity High fat diets, not calories, predispose to increased weight Prime example valproic acid, a short chained fatty acid, induces insulin resistance and consequent weight gain and a PCOS like hyperandrogenic clinical picture

9 Maternal calorie restriction Maternal diet (30% of the control) striking growth restriction, increased systolic blood pressures, increased fasting plasma insulin levels and hyperphagia Maternal diet decreased to 50% of the control during the last week of pregnancy and thru lactation associated with an age-dependent loss of glucose tolerance placental 11β-hydroxysteroid dehydrogenase type 2 decreased ---- resulting in high fetal glucocorticoid exposure

10 Maternal high-fat feeding High-fat feeding in pregnancy or lactation results in offspring hypertension, hyperinsulinemia and increased adiposity (Khan et al., 2005) 1.In humans High levels of dietary fat intake during gestation ---- increase the incidence of cardiovascular risk factors in children (Newman et al., 1986) 2.In rats Mothers fed high levels of saturated dietary fats: - fetal insulin resistance (Guo and Jen, 1995), - abnormal cholesterol metabolism (Brown et al., 1990) - go on to develop hypertension in adulthood (Langley- Evans, 1996)

11 Low-protein model rat studies: mimic catch up growth 8% protein diet (control: 20%) 15% birhtweight reduction Cross-fostered at birth to control dams Rapid postnatal catch-up growth during lactation 30 % reduction in longevity (renal failure) Low-protein rat model displays organselective growth.

12 Low-protein model -?Solutions Specific nutrients are important in preventing the detrimental effects of intrauterine growth retardation. Increased glycine hypertension Maternal Low protein diet Increased urea ---- Body weights of offspring are not reduced Supplement taurine --- rescue some of the effects on the fetus

13 Maternal Protein Deficiency Asymmetric Growth Restriction in Utero FOOD The Thrifty Phenotype CATCH-UP GROWTH BODY MASS # Nephrons Impaired Kidney Development # Nephrons (permanent) BP

14 The Link between Obesity & Relative Hyperinsulinemia with Hyperandrogenism Hyperinsulinemia: Most powerful contributor to accumulation of adiposity causes increased ovarian androgen production Adipose tissue is crucial in controlling the balance of sex hormone available to target tissues Can store androgens and estrogens and thereby affect Sex hormone binding globulin (SHBG) Estrogens, iodothyronines & GH stimulate SHBG Androgens & insulin inhibit SHBG production worse with central obesity so higher free androgen level Thus Androgen Excess a feature of insulin resistance/hyperinsulinemia and obesity

15 Leptin Leptin is a key metabolic signal synthesized and secreted by fat cells Communicates information about body energy reserves, nutritional state & metabolic shifts to the reproductive axis Acts at the hypothalamus and at the ovary In the hypothalamus, leptin stimulates Kisspeptin neurones Severe variations in leptin levels or altered sensitivity to leptin is mediated via the kisspeptin neurones to cause hypogonadotropism and infertility

16 Role of Leptin In Growth & Reproduction

17 Interaction between reproductive axis and obesity Solid arrows stimulatory; Dotted inhibitory Kiss 1: Kisspectin neurone

18 Interaction between Reproductive Axis (GnRH neuron) and Obesity Interaction according to estrogenic status. Solid arrows : stimulatory; dotted arrows :inhibitory. High E2 or Low E2 denotes the estogenic status in which the specific activity is taking place. α-msh:α-melanocyte stimulating hormone; GALP: galanin-like peptide;; NPY: neuropeptide Y

19 The role of obesity in PCOS.

20 Which comes first, the hyperinsulinemia or the hyperandrogenism? There are 6 reasons that hyperinsulinemia causes hyperandrogenism The administration of insulin to women with PCOS increases circulating androgen levels The administration of glucose to women with PCOS increases the circulating levels of both insulin and androgen Weight loss decreases the levels of both insulin and androgens In vitro, insulin stimulates thecal cell androgen production The experimental reduction of insulin levels in PCOS women reduces androgen levels After normalisation of androgens with GnRH agonist treatment, the hyperinsulinemic response during the OGTT remains abnormal in obese women with polycystic ovaries

21 OGTT in PCOS Chang et al 1983, JCEM, 57:356

22 Interaction between Androgens & Obesity

23 Effects of Fetal Androgen Excess

24 Prenatal androgen excess and the development of PCOS phenotype.

25 Plausible biological mechanisms in utero for development of MS: An adverse intrauterine nutritional milieu o Maternal/in utero malnutrition induce Epigenetic modifications which facilitate ooptimized use of reduced nutrient supply to ensure survival oblood flow redistribution in favor of vital organs ochanges in the production of fetal and placental hormones controlling fetal growth, odecreased basal metabolic rate and decreased nutrient delivery to tissues by reducing the capillary network.

26 Effect of Maternal/in Utero Malutrition, & Chronic Inflammation on Fetal Skeletal Muscle Development Glucose Consuming Tissue Glucose Storing Tissue Du M et al: Bio. Repro ; 82:

27 PRKA* Myogenesis and Adipogenesis NORMAL: Increase in PRKA increases suppression of ACACA thereby increasing myogenesis and limiting intramuscular lipid accumulation Maternal /Fetal malnutrition & chronic inflammation decreases PRKA thereby decreasing myogenesis and facilitating intramuscular lipid accumulation insulin resistance METFORMIN increases PRKA * Protein Kinase Activation previously called AMP activated protein kinase (AMPK) Du M et al: Bio. Repro ; 82:

28 In Vivo Evidence for the Developmental Origins for PCOS Testosterone (T) is high in mid-gestational amniotic fluid obtained from daughters of pregnant women with PCOS T concentration is high in umbilical cord blood from girls born to pregnant PCOS women High circulating AMH in infant daughters of women with PCOS Increased incidence of PCOS in women with CAH or fetal T-secreting tumor(fetal T excess) Thinness at birth associates with the presence of all 3 PCOS diagnostic criteria in adulthood High birth weight associates with hyperandrogenism in adulthood

29 Interesting Clinical Sign Trivia? Fetal androgen exposure is associated with phalangeal bone growth In Males ratio of the length of the 2 nd digit (index finger) & 4 th digit (ring finger) is lower than in females Male like low 2 nd to 4 th digit ratio is often found in women with PCOS 2 nd to 4 th digit ratio positively correlates with adult T levels in PCOS

30 The Metabolic Reproductive Syndrome = PCOS

31 Life Long Repercussions of Fetal Nutrition

32 You are Your Mother s Child

33 Teleological Explanation for Insulin Resistance and PCOS For successful survival in a nutritionally deprived environment the organism (human) : has to limit calorie requirements thus the decrease in stem cell commitment to myogenic fuel consuming tissues Has to have an increased capacity to store calories thus the increased commitment to adipocyte fuel storing tissues However, if the environment changes to a nutritionally surfeit state, the decreased volume of fuel consuming tissue is quickly overwhelmed and fuel storage accelerates predisposing to obesity

34 Adverse Effects of Obesity on Reproductive Function Polycystic ovary syndrome is associated with hyperinsulinemia and insulin resistance Results in disordered energy expenditure, characterized by reduced post-prandial thermogenesis. In addition hyperinsulinemia and obesity engender hyperandrogenism It is proposed that these closely interlinked phenomena in overweight subjects, are associated with anovulation BUT TELIOLOGICALLY IN A NUTRITIONALLY DEPRIVED ENVIORNMENT There is no hyperinsulinemia and no obesity and consequently no increased androgens allowing for ovarian function to be normal in the face of food deprivation This may confer a biological advantage for women with PCOS at times of food deprivation, when such women may reproduce more successfully than those without PCOS.

35 Proposed mechanism for the role of hyperinsulinemia in the etiology of anovulation in polycystic ovary syndrome

36 Life cycle chain of risk for dietrelated chronic diseases

37 Causes and consequences of intrauterine programming Fowden AL et al:physiology ; 2006 (21) 1, 29-37

38 Polycystic ovary syndrome (PCOS) 5-10% of women in the reproductive age Hyperandrogenism Amenorrhoea Anovulation Infertility Obesity

39 Causes of hyperandrogenism: PCOS 75% Idiopatic hirsutism 15% Adrenal hyperplasia 3% Cushing s disease 1% Hyperprolactinemia 1% Tumor of the ovary 1% Tumor of the adrenal 0.1% After medications 1%

40 Constitutional hirsutism Women with greater activity of 5 α reductase in the skin Normal ovulation Regular menstrual cycle Normal hormone concentrations

41 Sign and symptoms of PCOS patients Observation Average incidence Infertility 75% Hirsutism 56% Amenorrhea 47% Obesity 33% Regular menses 16% Virilisation 17%

42 Hyperandrogenism- clinical symptoms: Irregular menstrual cycles Hirsutism Acne Clitoromegaly Alopecia Deepening of the voice Androgenic body habitus Increased muscular mass Infertility

43 Clinical Hyperandrogenism-Hirsutism The cutaneous manifestation of high androgens Characterized by male-pattern hair growth in women Distribution : upper lip chin sideburn area upper neck chest upper arm lower abdomen intergluteal region perineum thigh Hirsutism rating scale by Ferriman Gallwey >8 points - hirsutism

44 Androgens are C-19 steroids: Androgens are produced in the: Ovary Adrenal gland Androgens are metabolised in: Skin Adipose tissue Liver Placenta

45 The main androgens Dehydroepiandrosterone (DHEA)-a weak carbon-5 androgen secreted principally by the adrenal gland Androstendione (A) - a weak carbon-4 androgen secreted in equal amounts by the adrenal glands and ovaries Testosterone (T)- a potent carbon-4 androgen secreted by the adrenal glands and ovaries and produced in adipose tissue from the conversion of androstendione Dihydrotestosterone (DHT)-even more potent than testosterone.the conversion from testosterone is the result of action of 5 α reductase

46 Origin of circulating androgens ADRENAL CORTEX 25% 50% 90% 99% 50% Testosterone Androstendione DHEA DHEAS 25% 50% 10% OVARY

47 The production rate of testosterone in the normal female is 0.2 to 0.3 mg/day Normal total testosterone concentration in serum is below 60 mg/dl

48 Testosterone is transported: High testosterone lowers SHBG causing higher levels of free hormone 1% Free 2% Free 19% Albumin 19% Albumin 80% SHBG 79% SHBG Normal women Hirsute women

49 Endocrine abnormalities in PCOS testosterone or normal LH/FSH ratio Normal Estrogens SHBG or normal Insulin or normal Prolactin or normal DHEAS AMH

50 Anti-Mullerian Hormone (AMH) AMH is expressed in pre-antral and small antral follicles; Expression disappears in maturing pre-ovulatory follicles Thus AMH a good indicator of the size of the ovarian antral follicle pool The density of pre-antralfollicles is six x higher in PCOS compared with normal ovary so AMH concentrations higher. Webber et al, 2003 As well, PCOS follicles produce more AMH?due to insulin?androgen The 2-5mm follicle pool is an independent contributor to the follicular arrest in PCOS.

51 AMH levels in Normal, PCO like, & PCOS patients Homburg et al, Hum Reprod,2013 Groups No Age BMI AMH (pmol/l) Controls (3.3) 24.8 (2.6) 23.6 (15.0)* PCOM (4.2) 24.7 (2.6) 52.2 (35.0)** PCOS (4.4) 24.9 (2.4) 77.6 (61.0)*** P NS NS PCOM vs PCOS Controls vs PCOM Controls vs PCOS Serum AMH concentrations are capable of differentiating between normal ovaries, PCOM and PCOS. The number of small follicles determines the severity of the syndrome.

52 PCOS study Correlation of Hirsutism, BMI,Insulin, F-G Score Androgens and AMH < >13 n age * 26* 27* BMI * 24.1* 26.4** 29.0** TSH * 2.7** 3.2** Testo Insulin * ** AMH * 4.70* Kulkarni et al:clin Endo&Metab US

53 Possible role of AMH in the pathophysiology of PCOS The size of the 2-5mm follicle pool is an independent and important contributor to the follicular arrest of PCOS. (Dewailly et al, 2007) AMH concentrations are very high in PCOS. The higher the AMH, the greater the ovulatory disturbance. (Pignyet al, 2006) Action of FSH in promoting follicular growth is counteracted by AMH. (Pignyet al, 2003;Weenen et al, 2004; Durlingeret al, 2001)

54 Mechanism of Anovulation in PCOS Androgen excess LH +insulin Multiple small follicles AMH FSH action Anovulation progesterone

55 Characteristic of the polycystic ovary The surface area is doubled The number of growing and atretic follicles is doubled (Each ovary may contain cystic follicles) The thickness of the tunica is increased by 50% There are 4 times more ovarian hilus cell nests

56 The Polycystic Ovary on ultrasound The ovaries have pericentric cysts of 5 to 10 mm - usually at least in one sonographic plane Increased ovarian stroma Only 75-80% women with the clinical diagnosis of PCOS had polycystic ovary Prevalence of polycystic ovary characteristics in 16 to 23% of normal women Seen in: up to 50% women with hyperprolactinemia 24% of women with hypothalamic amenorrhoea 100% of women with CAH

57 Ovarian defect in the pathogenesis of PCOS There is a hypothesis that hyperinsulinemia stimulates ovarian cytochrome P450c17α Dysregulation of cytochrome P450c17α results in : increased activity of 17α hydroxylase disordered 17,20-lyase activity excessive ovarian androgen production Defect in 3β-hydroxysteroid dehydrogenase or aromatase activity

58 Genetic defects of insulin receptor Defects of tyrosine kinase Autoantibodies to insulin receptor Insulin resistance Hyperinsulinemia SHBG Ovarian insulin receptors LH/FSH Ovarian IGF-I receptors IGFBP-1 IGF1 Free Testosterone Ovarian stimulation PCOS Hyperthecosis Hyperandrogenism

59 The clinical consequences of chronic anovulation in PCOS women Infertility Oligomenorrhea and amenorrhea Hirsutism and acne An increased risk of endometrial cancer An increased risk of cardiovascular disease An increased risk of diabetes mellitus in patients with hyperinsulinemia

60 Two Clinical categories of Functional Ovarian Hyperandrogenism Hyperandrogenism Hyperandrogenism with insulin resistance without insulin resistance Testosterone Elevated Elevated Fasting insulin Elevated Normal or minimally elevated LH Minimally elevated Markedly elevated LH response Normal Exaggerated to GnRH DHEAS Low-normal Normal or elevated Ovarian pathology Stromal hyperthecosis & PCOS Polycystic ovaries

61 Differentation of hyperandrogenism Diagnosis Menstrual Total DHEAS LH 17OHProg Source of Pattern Testoste- Androgens rone PCOS Irregular Elevated Elevated Elevated Normal OVARY Hyperthecosis Amenorrhea Elevated Normal Normal Normal OVARY often>1.5 ng/ml Idiopatic Regular Normal Normal Normal Normal SKIN hirsutism Adrenal Irregular Elevated Variable hyperplasia Usually Elevated ADRENA Normal >2ng/ml at 8am in follicular phase

62 Biochemical Evaluation of PCOS Lipids hi Tg lo HDL suggesting insulin resistance Fasting glucose? HbA?? Fasting Insulin Testosterone/free Testosterone DHEAS Androsteindione Of little to no added benefit Early morning early follicular phase 17-OH Progesterone: NC-CAH FSH (if amenorrhea):lh/fsh ratio of no help except in lean PCOS Anti Mullerian Hormone higher in PCOS Prolactin elevated in 15-30% of patients with PCOS mainly <50 TSH

63 Goals of Therapy in PCOS Reduce serum androgens Improve reproductive function Decrease risk for endometrial cancer Ameliorate complications putatively due to insulin resistance Glucose intolerance Dyslipidemia Hypertension Atherogenesis Promote weight loss

64 THERAPEUTIC OPTIONS GENERAL NON PHARMACOLOGIC MEASURES : Optimizing weight: Diet : restricted carbohydrates and calories Exercise: Daily, mins, low resistance, high frequency Manage hair: Bleaching Cutting or shaving Electrolysis Laser epilation Vaniqua cream 64

65 Local Skin Management Topical Therapy (Anti Comedonal Agents) Topical Retinoids % - 0.5% at night Avoid in pregnancy Azelaic acid 20% twice daily Salicylic acid 0.5-2% twice daily Topical Therapy (Anti Inflammatory Agents) Benzoyl Peroxide % once or twice daily Topical antibiotics - Clindamycin and Erythromycin twice daily Combination Benzoyl peroxide & local antibiotics Systemic therapy Oral Antibiotics the cyclines or erythromycin : 1-2/day x3-6m Isotretinoin - Accutane

66 THERAPEUTIC OPTIONS FOR HIRSUTISM SELECTING THE MOST APPROPRIATE MEDICAL THERAPY: Correct underlying medical problem Correct thyroid/hyperprolactinemia PCO :oral contraceptives (OCP) OCP + spironolactone is usually the choice 75 80% patients shows response At least 6 months is needed for evidence of response 66

67 THERAPEUTIC OPTIONS: OCPs Management of excess ovarian androgen production Standard therapy is combined E+P, most commonly OCPs Reduce ovarian androgen production by suppressing pituitary gonadotropins Increase SHBG: Estrogen effect & decreased androgens Induces competition at the cellular level for binding to the androgen receptor 67

68 THERAPEUTIC OPTIONS Choice of OCP EE + Norgestimate approved in USA Cyproterone acetate used as progesterone component in OCPs outside the USA EE + Spironolactone derivatives Some controversy but meta-analysis against other therapeutic modalities show OCPs more beneficial for control of androgens/hirsutism 68

69 THERAPEUTIC OPTIONS androgen receptor competitors Management directed to the target organ and cells SPIRONOLACTONE: Best studied and is considered the Gold standard Mechanism : Androgen receptors blockade Suppression of Androgen biosynthesis Increased metabolic clearance of testosterone ( Testosterone Estrogen ) mg/day in two divided doses Spironolactone + OCP is a well established regimen CYPROTERONE ACETATE: Blocks androgen action by competitive binding to the androgen receptor in the pilo-sebaceous unit Not licensed in the USA 69

70 THERAPEUTIC OPTIONS androgen receptors competitor FLUTAMIDE : Blocks the androgen receptors Decreases androgen production May have therapeutic value in cases of PCOS Usually used with OCPs Some danger of liver toxicity Frowned on by the FDA KETOCONAZOLE: Equally effective but danger of liver toxicity and adrenal blockade Frowned on by the FDA FINESTERIDE: 5-alpha reductase Inhibitors works in the skin to block conversion of testosterone to DHT frowned on by the FDA 70

71 THERAPEUTIC OPTIONS Responses are rarely seen quicker than 6-8 months Response is evaluated by: Rate of growth decreased frequency of local depilation procedures Texture of the hair less coarse, less pigmented Decreased density of the hair Less discrete areas of hair growth The latter 2 are later manifestations of response Positive responses indicate continuation of treatment In most cases treatment needs to be for a number of years Discontinuation is usually associated with relapse 71

72 THERAPEUTIC OPTIONS Pure DHEAS elevations with Normal Testosterone values may present with ACNE alone, Have minimal features of PCOS or insulin resistance Require LOW DOSE STEROIDS (Prednisone 2.5 mg qpm or bd OR Dexamethasone mg qpm) usually for mths. At these doses, minimal suppression of the HPA axis In over 50%, stopping steroids after 2-3 yrs is not associated with a recurrent increase in DHEAS Lo dose steroids are not universally accepted as appropriate treatment modalities

73 THERAPEUTIC OPTIONS OVARIAN SUPPRESSION BY LONG ACTING GnRH ANALOGUES Can be used for functional ovarian androgen overproduction and even for some malignant conditions But long term use requires concomitant OCPs Osteoporosis risk FDA recommends no more than 6 mths of therapy No evidence that this therapy is superior to OCPs 73

74 Treatment of infertile PCOS women Treatment of hyperinsulinemia Weight loss Metformin, TZD? Induction of ovulation Clomiphene citrate Letrozole Gonadotropins Surgical treatment Ovarian wedge resection by laparotomy Ovarian wedge resection by laparoscopy Ovarian cauterisation by laparoscopy

75 THERAPEUTIC OPTIONS INSULIN SENSITIZING AGENTS: For PCOS with/without acanthosis nigricans Commonly used agent is Metformin The glitazones (Pioglitazone & Rosiglitazone) work but contraindicated for pregnancy Metformin is licensed for use in type 2 DM Inhibits hepatic glucose production Suppresses intestinal glucose absorption Increases insulin sensitivity in peripheral tissues Regulates lipid metabolism NOT licensed for use in PCOS, BUT

76 Metformin in PCOS therapy Improvement in insulin sensitivity, hyperinsulinemia and androgen levels Velazquez et al. 1994, Metabolism, 43, ;Velazquez et al. 1997, Metabolism, 46, 454-7; Nestler et Jakubowicz, N Engl J Med., 335, Significant decrease in BMI and WHR Velazquez et al. 1994, Metabolism, 43, Improvement in menstrual regularity Morin-Papunen et al..1998, Fertil Steril, 69, 691-6, Velazquez et al. 1997, Obstet Gynecol, 90, No beneficial effects in some studies Acbay et al,1996 Fertil Steril, 65, 949-9; Ehrmann et al., 1997, JCMB, 82, Much less effects on clinical parameters : hirsutism and acne

77 Effect of metformin therapy on insulin Insulin before treatment Insulin after treatment Insulin(µU/ml) * 5 0 mean +/_ SEM * statistically different, p<0,001

78 Effect of metformin therapy on testosterone Testosterone (ng/ml) 1,4 1,2 1 0,8 0,6 0,4 0,2 Testosterone before treatment Testosterone after treatment * 0 mean +/_ SEM * statistically different, p<0,001

79 Effect of metformin therapy on SHBG SHBG (nmol/l) SHBG before treatment SHBG after treatment * 0 mean +/_ SEM * statistically different, p<0,05

80 Effect of metformin therapy on FTI FTI before treatment FTI after treatment 15 * FTI mean +/_ SEM * statistically different, p<0.001

81 Effect of metformin therapy on LH, FSH and LH/FSH ratio Before treatment After treatment LH (miu/ml) 10 5 FSH (miu/ml) 10 5 LH/FSH LH FSH LH/FSH 0 mean +/_ SEM

82 Effect of metformin therapy on body mass index BMI (kg/m2) BMI before treatment BMI after treatment * mean +/_ SEM 0 * statistically different, p<0.005

83 Effect of metformin therapy on lenght of menstrual cycle Lenght of menstrual cycle (days) * statistically different, p<0,001 Lenght of cycle before treatment Lenght of cycle after treatment * mean +/_ SEM

84 Effect of metformin therapy on WHR 1,2 1 0,8 WHR before treatment WHR after treatment * WHR 0,6 0,4 0,2 0 mean +/_ SEM * statistically different, p<0.001

85 METFORMIN VS OCP: HIRSUTISM Castello MF et al: Hum Reprod: 22; , 2007

86 METFORMIN VS OCP: ACNE Castello MF et al: Hum Reprod: 22; , 2007

87 METFORMIN VS OCP: TYPE 2 DM Castello MF et al: Hum Reprod: 22; , 2007

88 METFORMIN VS OCP:IMPROVED MENSTRUAL FUNCTION Castello MF et al: Hum Reprod: 22; , 2007

89 METFORMIN VS OCP: TESTOSTERONE Castello MF et al: Hum Reprod: 22; , 2007

90 METFORMIN VS OCP: FASTING INSULIN Castello MF et al: Hum Reprod: 22; , 2007

91

92 Metformin during Gestation Rat Study Female mice on a high fat diet (HFD) prior to & during gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Prenatal metformin changed the offspring's response to HFD: Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. CONCLUSION: Prenatal metformin exposure maintained a more normal glucose tolerance and fat mass accumulation during HFD in the offspring.

93 Results of clomiphene therapy in PCOS patients Ovulation 80% Pregnancy rate 75% Pregnancies/ovulatory cycle 25-35% Multiple pregnancies 8% Abortion rate 30-40%

94 LETROZOLE vs CLOMIPHENE (First-line) Letrozole 5 mg/d (n=218) Clomiphene 100 mg/d (n=220) P No. of follicles 4.4± ± Endom. Thick. (mm) 8.1± ± Serum E2 (pg/ml) 255.1± ± Serum P4 (ng/ml) 7.1± ± Days of stimulation 12.1± ± Preg./cycle 82/540 (15.1%) 94/523 (17.9%) Miscarriage/patient 4 (12.1%) 4 (9.7%) Badawy et al., 2007 Fertil. Steril. doi: /j.fertnstert

95 4 RCTs LETROZOLE IN PCOS Meta-analysis Letrozole vs CC Ovulation (OR 1.17, 95% CI 0.66 to 2.09) Pregnancy/cycle (OR 1.47, CI 0.73 to 2.96) Pregnancy/patient (OR 1.37, CI 0.70 to 2.71) Requena et al., 2008 Hum. Reprod. Update 14,

96 Results of gonadotropin therapy in PCOS women Ovulation 90% Pregnancy rate 70% Pregnancies/ovulatory cycle 25-30% Multiple pregnancies 10% Abortion rate 25-30%

97 Women with PCOS have a higher incidence of ovarian hyperstimulation syndrome after ovulation induction/stimulation

98 Hyperandrogenism and menopause The high circulating LH levels activates ovarian stroma and hilus cells steroidogenesis The menopausal ovary is a major source of testosterone, secretes moderate amounts of androstendione The pattern of androgen secretion is changed: Before menopause After menopause A>>T T>A

99 Age related Increased risk of diabetes mellitus in PCOS women PCOS Age WHR / / Diabetes (%) Controls Age WHR / / Diabetes (%) Dahlgren, Acta Obstet Gynecol Scand,1992,71,599

100 What s in a Name? There is a move to change the name of this syndrome from: Polycystic Ovary Syndrome, to The Metabolic Reproductive Syndrome: Is this a Conceptual Change or Just a Change of Name? I would suggest that it is more than just a change of name! It IS a conceptual change: PCOS describes an anatomic abnormality associated with sex hormone changes predisposing to cosmetic and reproductive dysfunction The Metabolic Reproductive Syndrome describes a more global reproductive and metabolic dysfunction adversely affecting the total life span of affected women!

101 Conclusions - 1 There is strong evidence for a relationship between insulin resistance and PCOS Justifying a name change to The Metabolic Reproductive Syndrome The syndrome develops as an intrauterine genetic adaptation for putative lifetime nutritional deprivation Manifests due to a change in the environment to a nutritionally replete state

102 Conclusions - 2 Initial biochemical evaluation, after a clinical evaluation, includes androgens, prolactin, TSH & metabolic parameters Treatment includes: Non pharmacologic life style changes Treatment of the metabolic derangements Treatment of PCOS according to the patient s need: cosmetic; hormone suppression and local skin therapy reestablishment of cycles for fertility Metformin offers promise as a first-line adjunct to diet & exercise & can ameliorate anovulation, hyperandrogenism, & metabolic abnormalities

103 QUESTION 1 Anovulatory infertility in PCOS is due to all except: A) Alterations of folliculogenesis caused by dysregulation of the GnRH pulse generator B) Alterations of folliculogenesis caused by ovarian and adrenal hyperandrogenism C) Alterations of folliculogenesis caused by insulin resistance D)Alterations of folliculogenesis caused by an insulin dependent decrease in ovarian growth factors E) Alterations of folliculogenesis caused by hyperestrogenism

104 QUESTION 2 One of the following statement concerning the pathogenesis of PCOS is true: A) There is an intrinsic insulin signaling ovarian theca cell defect leading to androgen overproduction B) There is impaired hypothalamic-pituitary sensitivity to ovarian steroid feedback C) There is a primary defect of gonadotropin synthesis leading to a preferentially increased LH synthesis D) The increased LH concentrations may result from the androgen induced impairment of hypothalamic sensitivity to ovarian steroid feedback E) It results from a primary hypothalamic defect leading to increased GnRH pulse generator frequency

105 QUESTION 3 All of the following factors have been implicated in the pathogenesis of PCOS except: A) Low birth weight B) High birth weight C) Intrauterine androgen excess D) In vitro fertilization E) Maternal diabetes

106 QUESTION 4 Biochemical abnormalities seen in PCOS include: A) Very low serum FSH concentrations B) Low serum estrogens C) High sex hormone binding globulin (SHBG) D) High 17 hydroxyprogesterone E) High AMH

107 QUESTION 5 Oral Contraceptives improve hirsuitism and acne by what mechanism(s)? A) Progestogens increase serum levels of SHBG B) Ethinyl estradiol, but not progestogen, lowers LH and FSH secretion C) Progestogens inhibit 5α-reductase activity D) In PCOS, oral contraceptives improve insulin resistance, which may lessen the impact of excess androgen production

108 QUESTION 6 The following are true about small antral follicles (2-9mm) in PCOS except: A) They are increased in number compared to normal ovaries B) They are at increased risk of apoptosis when compared to same sized follicles in normal ovaries C) They are a source of excess androgen production in both ovulatory and anovulatory women with PCOS D) They are a source of excess AMH production E) In vitro studies have shown that in anovulatory women the granulosa cells of these follicles respond to LH stmulation at an earlier stage of follicular development (4mm diameter) when compared to granulosa cells obtained from ovulatory subjects

109 QUESTION 7 All of the following are true with regards to the metabolic syndrome & PCOS except: A) 46% of women with PCOS also have the metabolic syndrome B) There is considerable overlap between PCOS and the metabolic syndrome C) Coagulopathy is not a feature of the metabolic syndrome and PCOS D) Metabolic abnormalities improve as the ratio of visceral-to-subcutaneous fat decreases E) Improvement in insulin sensitivity and free fatty acid levels following reduction in visceral obesity after weight loss have been demonstrated

110 QUESTION 8 Approximately 50% of PCOS women are obese. Obesity is a key factor in determining risk for cardiovascular disease. When considering obesity and PCOS all are true EXCEPT: A) Central distribution of adipose tissue can be inferred clinically by a waist to hip ratio of greater than 0.85 B) A majority of non-obese PCOS women have a waist to hip ratio of greater than 0.85 C) Lean PCOS women are metabolically normal D) Defects in visceral cell lipolysis have been demonstrated in non-obese PCOS women E) Obesity is the most important determinant of risk for the development of hypertension, hyperinsulinemia, and dyslipidemia in an aging population of PCOS patients

111 ANSWERS Q 1) D Q 2) A Q 3) D Q 4) E Q 5) C Q 6) B Q 7) C Q 8) C