Polycystic Ovarian Syndrome Omar Al Omari, MRCOG Obstetrician & Gynaecologist Jordan Hospital Medical Center FQN0009

Polycystic Ovarian Syndrome 1st 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, 1998. Azziz R et al, Journal of Clinical Endocrinology & Metabolism, 2004. Opening to lecture. Polycystic Ovarian Syndrome was first recognized by Stein and Leventhal who observed the relationship between obesity and reproductive disorder, what is now known as the “syndrome O” (over-nourishment, overproduction of insulin, ovarian confusion, and ovulation disruption). Since then, this condition is considered to be the most common endocrine disorder of pre-menopausal women, affecting an estimated 5% of the population. Current literature has suggested a higher frequency range (5-10%) through investigations into ethnicity including Hispanic/Latino females who are at an increased risk of diabetes. May ask for feedback from the audience. Goodarzi MO et al, Fertility and Sterility, 2005. Ehrmann DA, New England Journal of Medicine, 2005.

Review Objectives Symptom Presentation Diagnosis Definitions Potential Causes Metabolic and Reproductive Complications Infertility Lecture Synopsis. The objective of this review is to briefly address the current knowledge of diagnosis, cause, complications, and infertility treatment.

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 growth Abnormal bleeding Obesity Hair loss Acne Infertility Review Symptoms and Signs. PCOS is heterogeneous endocrine disorder, a syndrome not a disease, in which no single criterion is sufficient for diagnosis due to the multiple etiologies and presentations. Defining characteristics include menstrual dysfunction, hyperandrogenism, ovarian morphology on U/S, with the exclusions of other endocrine abnormalities (Cushing’s syndrome, thyroid abnormality, hyperprolactinemia, etc.). May ask audience for features they have noticed in PCOS patients. 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) Intro to Criteria. Due to the heterogeneous presentation of the symptoms and variations observed in patients over time, two International meetings (National Institutes of Health (NIH) and European Society for Human Reproduction & Embryology/American Society for Reproductive Medicine (ESHRE/ASRM)) have been conducted in an attempt to create consistent guidelines. Other factors can impact clinical presentation of PCOS including ethnicity (rarely see hirsutism in Asian population), age (patients show improvement as approach menopause), or weight (worsen with weight gain and improve with weight loss). Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group, Fertility and Sterility, 2004.

Addition of PCO. As implicated through the addition of the PCO criteria, the ultrasound has provided a large contribution to diagnosis, monitoring and management of PCOS. Consensus definitions next slide. Balen AH et al4

Genetic Predisposition Android Obesity Genetic Predisposition Aging Pregnancy Drugs Lifestyle Insulin Resistance ↑ Lipid Storage Hyperinsulinemia Altered Fat Metabolism Altered Steroid Hormone Metabolism Insulin Effects. Looking at the effects of insulin in a larger scheme, this table adapted from Cristello and colleagues portrays the cascading consequence of life choices, aging and genetics leading to insulin resistance which progresses into other complications including PCOS. For examples, intrauterine environment may influence expression of PCOS resulting in prenatal exposure to androgens in offspring of PCOS mothers causing a stimulus for low birth weight (LBW) and development of PCOS. PCOS: Acne, hirsutism, hyperandrogenism infertility Adapted from Cristello F et al, Gynecological Endocrinology, 2005.

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 Early Signs. In the 1986 WHO-initiated work-up 2 years after menarche, many adolescents present with transitory functional hyperandrogenism. Hyperandrogenism – increased T due to increased insulin and LH in obese peripubertal girls (decreased SHBG). With the increase of childhood and teenage obesity in America, recent pediatric literature has asked if PCOS is being misdiagnosed as part of puberty. Earlier work-up, initiated more rapidly by the presentation of obesity, now examines girls 12-18 months after menarche-especially if LBW, family HX of PCOS, abdominal obesity. Guttmann-Bauman I, Journal of Pediatric Endocrinology & Metabolism, 2005.

Genetic Link Familial clustering of PCOS common 1st 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 Yildiz BO et al, Journal of Clinical Endocrinology & Metabolism, 2003. “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.” Heritability. Due to the observable trends within families concerning insulin resistance, the question remains whether PCOS has a genetic connection. For instance, first degree relatives inherit B-cell dysfunction (secretory deficits). Franks and colleagues offered the following hypothesis: Linage analysis-syndrome inherited in autosomal recessive fashion; heterogeneous disorder-need to focus on hyperandrogenism to assign phenotype. Franks S et al, International Journal of Andrology, 2006.

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, 1997. Ehrmann DA et al, Diabetes Care, 1999. Legro RS et al, Journal of Clinical Endocrinology & Metabolism, 1999. Other Complications. As insinuated by the insulin resistance, PCOS is not just a reproductive disorder but a multifaceted metabolic disorder. Review stats given. Obesity is also a feature observed, estimated to effect 50% of PCOS women, classically presented in patients with upper body obesity which has been associated to menstrual disturbances (Hartz et al. Int J Obes. 3:57; 1979). In the older literature, obesity was thought to be the cause of PCOS; it is now understood that obesity is a modifier of the condition. It should also be pointed out that obesity is also considered in some literature to be an environmental factor, i.e. lifestyle. Obesity is also a feature observed, originally estimated to effect 50% of PCOS women, classically presented in patients with upper body obesity which has been associated to menstrual disturbances (Hartz et al. Int J Obes. 3:57; 1979). In the older literature, obesity was thought to be the cause of PCOS; it is now understood that obesity is a modifier of the condition. It should also be pointed out that obesity is also considered in some literature to be an environmental factor, i.e. lifestyle. Obesity in US higher than Europe: Central obesity-waist circumference >35 inches (88 cm). Goldzieher JW, Young RL, Endocrinology Metabolism Clinics of North America, 1992. 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, 2000. Pillay OC et al, Human Reproduction, 2006. Other Complications. Endometrial cancer (EC): Due to the high estrogen levels and lack of normal ovulation cycles, there is a risk for endometrial cancer in PCOS women. Endometrial cancer-described as early as 1949 by Speer-cystic ovaries and EC-persistent estrogen stimulation; hyperplasia-lack of differentiation to secretory endometrium. Prolonged stimulatory effect of estrogen with unopposed inhibition by progesterone. Cardiovascular disease (CVD): Putting into consideration the rates of insulin resistance and obesity together plus the complications of high blood pressure and increased lipids values, PCOS patients are also at risk for CVD. CVD-associated with both increase in androgen and IR-increase in levels of inflammatory cytokines-IL6, TNF alpha-increased lipids, BP, obesity, IR-associate with CVD. Higher BMI-greater risk for both conditions. Paradisi G et al, Circulation, 2001. Dahlgren E et al, Acta Obstetricia et Gynecologica Scandinavica, 1992.

PCOS: Metabolic Disorder 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, 2005. Rasgon NL et al, Journal of Affective Disorders, 2003. Other Complications. Two other areas that have been associated to PCOS patients includes sleep apnea and depression effecting a woman’s productivity and quality of life. Apnea: Sleep apnea-greater in PCOS – greater than obesity alone, not correlate with BMI. Gender difference of sleep-disordered breathing (SDB). Found more common in middle age obese men and infrequently in premenopausal, yet prevalent in PCOS even non-obese-related to IR measures-30-40X age & weight-matched controls. PCOS women-glucose tolerance is directly related to severity of SDB. SDB shown to exacerbate metabolic consequence of IR-accelerate conversion to IGT (Ehrmann 2006). Insulin levels and measures of glucose tolerance are correlated with risk and severity of obstructive sleep apnea which confirms a direct relationship between insulin levels and sleep apnea. Androgen not related. Emotional stress: PCOS can influence feminine identity-less satisfied with sex life despite same frequency of intercourse-50 PCOS, 50 control women-loss self worth-feel less feminine, different than other women even when control for BMI.

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, 2001. Turhan NO et al, International Journal of Gynecology & Obstetrics, 2003. Bjercke S et al, Gynecologic and Obstetric Investigation, 2002. Reproductive Complications. PCOS not only affects women pre-pregnancy but also post-pregnancy. Several studies have suggested various complications as listed here. Gestational Diabetes(GDM): Lo et al. examined 90,000 births with >5000 cases GDM. PCOS women had a 2.4 fold increased odds of GDM independent of age, race/ethnicity or multiple gestation (Diabetes Care, 2006). Small for Gestational Age (SGA): Polygenic genetically determined factors increase IR-impaired insulin-mediated growth. Environmental-metabolic programming-fetal exposure to sex steroids-maternal intrauterine environment. Although there is some literature that contradicts a few of these claims such as Haakova et al. Hum Reprod. 18:1438; 2003. May ask for audience feedback. Weerakiet S et al, Gynecological Endocrinology, 2004. 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, 2006. Webber LJ et al, Lancet, 2003. Infertility. Franks and colleagues suggested that over 75% of the patients with anovulation were PCOS patients. PCOS involves primary ovarian dysfunction. This intrinsic ovarian abnormality caused an increased density of small preantral follicles, primordial not different, same for ovulatory and anovulatory. Early follicular growth is excessive since the selection of 1 single follicle from the follicular pool to mature to the dominant one not occur. 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, 2005. Weight Loss. Tie in similarity of first line of treatment from previous slide. The most effective benefits are from the calorie-restricted diets which limiting “carbohydrates” rather than fats-reduction of insulin levels. In the Clark study, BMI was still >30, so still obese with weight loss, yet a 5% reduction in body mass was still able to restore ovulation. It is important to offer a program of exercise and sensible eating, plus educate women about long term adverse effects. Infertile women are usually highly motivated since they are also seeking a pregnancy. 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 Infertility Treatments. Another complicating feature of PCOS is the effects it has on ovulation and fertility. Since there are so many facets to PCOS, there are also multiple options for treating infertility based upon the patient’s characteristics. First line of treatment in overweight patients is weight loss through lifestyle modification. Another cautious approach is administering CC as first line then insulin sensitizer if REGNANCY desired outcome. However, only short-term treatment with sensitizer and although CC has demonstrated benefit it should be limited to three cycles (Gysler et al. Fert Ster 37:161; 1982). The infertility industry has developed multiple treatment protocols to offer women with PCOS. The following slides review two studies demonstrating the published success. 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 . . OHSS. Follicular arrest can be reversed by pharmacological manipulations with FSH. However the rescue may lead to OHSS, thus caution must be used. Although proper monitoring is key for preventing OHSS, other steps as listed here are also an option.

Conclusions PCOS is a multifaceted condition Infertility 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

Thank you Questions and Thank-you.