Polycystic Ovarian Syndrome FQN0009

Polycystic Ovarian Syndrome 1 st described by Irving Stein and Michael Leventhal as a triad of amenorrhea, obesity and hirsutism (1935) The most common endocrine disorder in women of reproductive age ~ 2%-8% of women Current suggested prevalence in the U.S. –Caucasian: 4.8% –African American: 8.0% –Hispanic or Latino: 13% –5%-10% of women Knochenhauer ES et al, Journal of Clinical Endocrinology & Metabolism, Azziz R et al, Journal of Clinical Endocrinology & Metabolism, Goodarzi MO et al, Fertility and Sterility, Ehrmann DA, New England Journal of Medicine, 2005.

Review Objectives Symptom Presentation Diagnosis Definitions Potential Causes Metabolic and Reproductive Complications Infertility

PCOS Presentation Two of the following symptoms: –Polycystic ovaries (PCO) –Hyperandrogenism –Anovulation No single criteria is sufficient for clinical diagnosis. Additional features may include: Excessive hair growthAbnormal bleeding ObesityHair loss Acne Infertility Azziz R, Obstetrics and Gynecology, 2003.

PCOS Presentation Difficult to diagnosis –Heterogeneous symptoms –Vary over time NIH-Sponsored Conference on PCOS (1990 Criteria) Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group (2003 Criteria) Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Fertility and Sterility, 2004.

Balen AH et al 4

Genetic Predisposition Aging Pregnancy Drugs Lifestyle Insulin Resistance Hyperinsulinemia Altered Fat Metabolism Altered Steroid Hormone Metabolism PCOS: Acne, hirsutism, hyperandrogenism infertility PCOS: Acne, hirsutism, hyperandrogenism infertility Adapted from Cristello F et al, Gynecological Endocrinology, Android Obesity Lipid Storage

Early Signs: Adolescence Polycystic ovarian syndrome is the most common endocrinopathy in adult women, and is emerging as a common cause of menstrual disturbances in the adolescent population Normal pubertal events include: Oligomenorrhea, hirsutism, acne, and weight gain –Insulin resistance has reportedly increased in last decade Pediatric Endocrinologists trending towards an earlier work-up then compared to traditional practice of waiting 2-years post- menarche Guttmann-Bauman I, Journal of Pediatric Endocrinology & Metabolism, 2005.

Genetic Link Familial clustering of PCOS common –1 st degree relatives of patients with PCOS may be at high risk for diabetes and glucose intolerance –Mothers and sisters of PCOS patients have higher androgen levels than control subjects Franks S et al, International Journal of Andrology, Yildiz BO et al, Journal of Clinical Endocrinology & Metabolism, PCOS is a genetically determined ovarian disorder… the heterogeneity can be explained on the basis of interaction of the disorder with other genes and with the environment.

PCOS: Metabolic Disorder Insulin Resistance –High association with PCOS –10% have Type 2 Diabetes –30%-35% have Impaired Glucose Tolerance (IGT) Obesity –50% of PCOD patients are obese –Amplifies biochemical and clinical abnormalities of PCOS Dunaif A, Endocrinology Review, Ehrmann DA et al, Diabetes Care, Legro RS et al, Journal of Clinical Endocrinology & Metabolism, Goldzieher JW, Young RL, Endocrinology Metabolism Clinics of North America, Kiddy DS et al, Clinical Endocrinology, 1990.

PCOS: Metabolic Disorder Endometrial Cancer –Long-term follow-up of 786 PCOS women found an increased risk of endometrial cancer –Women >50 yrs of age with endometrial cancer, PCOS (62.5%) more prevalent than not (27.3%; P=0.033) Cardiovascular Disease –PCOS is characterized by endothelial dysfunction and resistance to vasodilating action of insulin –Increased risk of myocardial infarction in PCOS women than age-matched controls Wild S et al, Human Fertility, Pillay OC et al, Human Reproduction, Paradisi G et al, Circulation, Dahlgren E et al, Acta Obstetricia et Gynecologica Scandinavica, 1992.

Sleep Apnea –Increased Sleep Disordered Breathing (SDB) and daytime sleepiness in PCOS vs. controls Depression –Higher prevalence in PCOS patients, associated with higher body mass index (BMI, P=0.05) and greater insulin resistance (P=0.02) Vgontzas AN et al, Sleep Medicine Reviews, Rasgon NL et al, Journal of Affective Disorders, PCOS: Metabolic Disorder

Pregnancy Complications Spontaneous Abortions –Increased in high BMI/PCOS patients Impaired Glucose Tolerance Gestational Diabetes Hypertension Small for Gestational Age Wang JX et al, Human Reproduction, Turhan NO et al, International Journal of Gynecology & Obstetrics, Bjercke S et al, Gynecologic and Obstetric Investigation, Weerakiet S et al, Gynecological Endocrinology, Sir-Petermann T et al, Human Reproduction, 2005.

Infertility >75% of women with anovulation infertility Follicular arrest – Impaired selection of dominant follicle –Risk of multiple pregnancy with treatment Franks et al, International Journal of Andrology, Webber LJ et al, Lancet, Jonard S, Dewailly D, Human Reproduction Update, 2004.

PCOS: Weight Loss Frequency of obesity in women with anovulation and PCO: 30%-75% Six month weight-loss program for overweight anovulatory women –Lost an average of 6.3 kg (13.9 lbs) –Decreased fasting insulin and testosterone levels –92% resumed ovulation (12/13) –85% became pregnant (11/13) Ehrmann DA, New England Journal of Medicine, Clark AM et al, Human Reproduction, 1995.

Infertility Treatments Step-by-step.... –If BMI elevated, loss of at least 5% body weight –Ovulation induction (OI) with clomiphene citrate –Insulin sensitizer as single agent –Insulin sensitizer + clomiphene –Gonadotropin therapy, FSH hormone –Gonadotropins + insulin sensitizer –In vitro fertilization (IVF) …single embryo transfer Kim LH et al, Fertility and Sterility, 2000.

PCOS: Stimulated Cycles PCOS patients are often high responders to medications, Clomid and FSH –High risk of multiple pregnancy –Ovarian hyperstimulation syndrome (OHSS) –IVF…single embryo transfer..

Conclusions PCOS is a multifaceted condition –Varying presentations –Begins in adolescence –Long-term consequences –Genetic and pre-natal implications –Metabolic Disorder –Cosmetic issues –Reproductive complications. cycle irregularity / bleeding / endometrial cancer Infertility –Common endocrinopathy in pre-menopausal women, causing menstrual irregularities and hirsutism –Multiple treatments available with potentially successful outcomes

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