1. Polycystic Ovary Syndrome
Ding Ding M.D., Ph.D.
Department of Obstetrics & Gynecology
Ob/Gyn Hospital
Fudan Unoversity

2. Introduction
Definition: polycystic ovary syndrome (PCOS) is a generic description for a broad spectrum of clinical and morphological findings in women with an endocrine dysfunction, specifically abnormal androgen production and metabolism.
PCOS was first identified by Stein and Leventhal in 1935 so that it can also be known as Stein – Leventhal Syndrome.
PCOS

3. 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
PCOS
Adapted from Cristello F et al, Gynecological Endocrinology, 2005.

4. Pathology Ovaries:bilateral enlarged and/or polycystic ovaries
endometrium: Lack of ovulation for an extended period of time may cause excessive thickening of the endometrium (the lining of the uterus).
PCOS

5. What Are the Symptoms of PCOS?
Oligomenorrhea:
Reduction in frequency of menses
Between 35 days and 6 months.
PCOS

6. Symptoms
Hirsutism : Excessive body hair. In women with PCOS dark, coarse hair will appear on the face, neck, chest, intergluteal, axillary and pubic area.
PCOS

7. Symptoms
Obesity
PCOS

8. Symptoms
Acne : Because women with PCOS are producing more androgen, that produces more sebum ( skin oils and old tissue) and causes blocked pores and more acne around the jawline, arms and chest.
PCOS

9. Other Symptoms
“Dirty Skin” or Acanthosis Nigricans : This condition causes light brown to black rough patches around the neck and under arms.
PCOS

10. Diagnosis BBT (basal body temperature) Ultrasound:
multiple small ovarian follicles
enlarged ovaries
Endometrium biopsy(Curettage )
before menses reveal to proliferative glands
Elevated free testosterone
LH:FSH≧3:1
10-30% hyperprolactinmia
hyperinsulinmia
Laparoscopy
PCOS

11. 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.
PCOS
Balen AH et al4

12. Polycystic Ovary
PCOS

13. PCOS: Metabolic Disorder
Insulin Resistance
High association with PCOS
10% have Type 2 Diabetes
30%-35% have Impaired Glucose Tolerance (IGT)
Obesity
50% of PCOS patients are obese
Amplifies biochemical and clinical abnormalities of PCOS
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).
PCOS

14. PCOS: Long-term Risks Cancer
Chronic anovulatory, persistently elevated estrogen levels, uninterrupted by progesterone, PCOS women found an increased risk of endometrial cancer
The risk of ovarian cancer is also increased two-to three fold
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
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.
PCOS

15. 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)
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.
PCOS

16. 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; May ask for audience feedback.
Weerakiet S et al, Gynecological Endocrinology, 2004.
Sir-Petermann T et al, Human Reproduction, 2005.
PCOS

17. Treatment: Weight Loss
calorie-restricted diets
Exercise
a 5% reduction in body mass was still able to restore ovulation
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)
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.
PCOS

18. Treatment Fertility Treatment
If pregnancy is desired induce ovulation
Clomiphene Citrate
Anti insuline resistance-Metformin mg/d
anti-androgens
Laparoscopic ovarian drilling (LOD): reduce ovarian sourced androgen
IVF
PCOS

19. Laparoscopic Ovarian Drilling
Lasers burn holes in enlarged follicles
Stimulates ovulation by reducing LH and androgen
Improve local microcirculation
PCOS
Mayo Clinic 2006

20. Treatment If pregnancy is not desired
to reduce the risk of endometrial cancer ( birth control pills)
OC: Diane-35: reduce LH and androgen
cyclical progesterone (Medroxyprgesterone)
Anti insuline resistance-Metformin mg/d, Glucophage
Anti-androgens
PCOS

21. Case presentation 22 y.o. college student, do not want to conceive
Obese, oligomenorrhea, LMP: 3 months ago
Hirsutism at face, axillary and pubic area
Face acne
Testosterone is mildly elevated
DHEAS is normal
LH 35mIU/ml, FSH 9 mIU/ml
Examination? Diagnosis? Treatment?
PCOS

22. Thanks for Your Attention
Ding Ding M.D., Ph.D.
Department of Obstetrics & Gynecology
Ob/Gyn Hospital
Fudan Unoversity