1. Current Concepts in Polycystic Ovarian Syndrome Mark N. Simon, MD Exempla Uptown Women’s Healthcare Specialists October 17, 2003

2. Disclosure Dr. Simon has no significant financial interests or other relationships with industry relative to the subject of this lecture.

3. Objectives Cite the physical manifestations of PCOS. Describe the pathophysiology of PCOS. Formulate a treatment plan for patients with PCOS.

4. Scope of the Problem PCOS is the MOST common endocrine disorder of reproductive age women Effects 5-10% of these women Commonly presents to primary care providers

5. Diagnosis North America (NIH Consensus): – Menstrual Irregularity (oligo- or anovulation) – Hyperandrogenism Clinical evidence OR Laboratory evidence – Absence of other endocrine disorders Congenital Adrenal Hyperplasia Hyperprolactinemia Thyroid dysfunction

6. Diagnosis Europe: – Morphological features of polycystic ovaries – Menstrual disturbance AND/OR – Hyperandrogenism Hirsuitism Acne Alopecia Laboratory data are not needed

7. Ultrasound Polycystic Ovaries – Found in around 20% of general population – May be a predictor of future development of PCOS – Found in 80% of women with PCOS Appearance – Many, peripheral, small follicles – Increased ovarian stroma

8. European Diagnosis Increases prevalence to about 15% Proposed unifying protocol: 1. Determine if symptoms are present 2. If present, proceed with ultrasound 3. If ultrasound positive – diagnosis confirmed 4. If ultrasound negative – check lab tests Homberg, Human Reproduction, 2002

9. Diagnosis North America (NIH Consensus): – Menstrual Irregularity (oligo- or anovulation) – Hyperandrogenism Clinical evidence OR Laboratory evidence – Absence of other endocrine disorders Congenital Adrenal Hyperplasia Hyperprolactinemia Thyroid dysfunction

10. Patient Presentation Symptoms of hyperandrogenism Irregular menstrual cycles Infertility – Most Common Presentation

11. Symptoms of Hyperandrogenism Hirsutism Acne Rarely see Virilization – Male pattern balding – Clitoromegaly – Deepening of voice – Increased muscle mass

12. Hirsutism Occurs in 80% of PCOS patients Excess terminal body hair – Male Pattern Back, Sternum, Upper Abdomen, Shoulder More common areas – Upper Lip, Around breast nipples, Linea alba – ¼ of women have hair in these areas Excluding Scandinavian, Asian

13. Hirsutism - DDx Idiopathic PCOS Drugs (Danazol) Hyperthecosis Ovarian Tumors Adrenal Tumors CAH

14. Ovarian Hyperthecosis Ovary has nests of luteinized theca cells Signs and Symptoms – Hirsutism, Alopecia, Obesity – HTN – Clitoromegaly – Markedly elevated testosterone

15. Red Flags with Hirsutism Rapid onset of hirsutism Rapid progression of hirsutism Late onset – Outside of early reproductive years Virilization

16. Tumors RED FLAGS Testosterone > 150ng/dL (> 200ng/dL) LH low DHES > 800mcg/dL Further investigation warranted – MRI abdomen/pelvis

17. Nonclassic Congenital Adrenal Hyperplasia Partial deficiency of 21-hydroxylase Elevation of 17-hydroxyprogesterone – Precursor of androgens Rare Do NOT have adrenal insufficiency Treat with anti-androgen therapy

18. Nonclassic Congenital Adrenal Hyperplasia Consider in patients not responding to typical PCOS treatment Measure 17-hydroxyprogesterone – Follicular phase – Morning – Levels > 2 ng/mL need to be tested further Adrenal stimulation

19. Acne Common in adolescent girls (30-50%) Severe acne is uncommon (<1%) Severe acne is a predictor of PCOS

20. Irregular Menses Most common to have erratic menses – Due to Anovulation Patients present with oligomenorrhea or amenorrhea

21. PCOS with Regular Menses? Androgens converted to estrogens – Peripheral conversion – Aromatase Estrogens stimulate uterine lining Can have regular shedding of endometrial lining despite anovulation

22. PCOS with Regular Menses? Hyperandrogenism does NOT automatically cause anovulation Women with hyperandrogenism and polycystic ovaries may still ovulate regularly Affect on fertility is unclear

23. Infertility Usually long-standing infertility PCOS typically develops in early reproductive years Infertility usually due to anovulation

24. Clinical Presentations Hyperandrogenism – Hirsutism – Acne Menstrual Irregularity Infertility

25. Initial Evaulation History to determine onset PCOS usually has long course – Rapid onset of hirsutism – Red Flag Usually develops early in reproductive years PCOS is diagnosis of exclusion Lab tests help to exclude other problems

26. What tests to order Prolactin – Rule out hyperprolactinemia – Cause of menstrual dysfunction – Little signs of hyperandrogenism – Lactotroph stimulation from estrogen Testosterone DHEAS

27. Laboratory Tests 17-Hydroxyprogesterone – In patients suspected of NCAH TSH – When symptoms warrant Glucose Tolerance Test Fasting Lipid Profile

28. Laboratory Tests LH, FSH – Little benefit Insulin

29. Pathophysiology Exact problems have not been identified Hypothalamic-pituitary abnormalities – Elevated LH Increased frequency and amplitude of pulses – Low-normal FSH – LH:FSH ratio increased – GnRH pulse generator may be disrupted causing the elevated LH

30. Hyperandrogenism Androstenedione – Produced in ovarian thecal cells – Production is stimulated by LH – Converted to estradiol by FSH-stimulated aromatase – Excess is converted to estrone which suppresses FSH and is tonic to LH

31. LH Ovary Androstenedione Estrone Estradiol FSH + - Hyperandrogenism Testosterone SHBG -

32. Insulin Resistance Feature of PCOS Both obese and lean women are affected Affects a number of systems Reduction in tissue response to insulin

33. Insulin Resistance Insulin causes androgen production – In women with PCOS Insulin – Amplifies LH response in granulosa cells – Arrest of follicular development

34. Insulin Resistance Insulin-like growth factor 1 (IGF-1) – Amplifies LH and androgen synthesis – Helps to regulate follicular maturation Insulin-like growth factor binding protein 3 (IGFBP-3) – Decreased in patients with ovarian hirsuitism – When decreased, more bioavailability of IGF-1 Shobokshi, et al, J Soc Gynecol Investig, 2003

35. Insulin Glycogenolysis Gluconeogenesis Peripheral Glucose Uptake - + -

36. Insulin Resistance Insulin Ovarian Androgen Secretion Anovulation Granulosa Cells +

37. Summary of Pathophysiology Elevated LH Leads to elevated Androgens – Hyperandrogen symptoms Insulin Resistance

38. Treatment Depends on symptoms Depends on patient’s goals

39. Lifestyle Modification Exercise – 150 minutes per week – Moderate exertion Diet Weight Loss Most effective with obese patients

40. Weight Loss Improves ovulatory and fertility rates – 5-7% loss – Restored ovulation in 75% Decreases LH pulse amplitude – Decreases androgen production Reduces insulin levels Kiddy et al., Clin Endocrinol, 1992.

41. Insulin Sensitizers Metformin – Most extensively studied – Increases peripheral uptake of glucose – Decreases gluconeogenesis – Does not cause hypoglycemia – Relatively inexpensive Generic 500mg, 60 tabs $33.99 (drugstore.com 10/15/03)

42. Metformin Side Effects – Gastrointestinal distress – Most common in first few weeks of use – Improves over time – Lactic acidosis Dosage is 500mg TID or 875mg BID

43. Metformin Lactic Acidosis – Severe, potentially fatal – Concern with elevated creatinine (>1.4 mg/dL) Contraindicated in – – CHF, Sepsis, Liver disease, history of lactic acidosis Surgery

44. Rosiglitazone Insulin-sensitizing agent Stimulate production of glucose transporter proteins Few studies in PCOS Dosage is 4mg BID More expensive – 4mg, 30 tabs cost $77.99 (drugstore.com, 10/15/03)

45. Rosiglitazone Improved clinical symptoms Corrects insulin resistance Improves ovulation rates Fewer side effects – Especially GI Fertility rates not studied Shobokshi, et al, J Soc Gynecol Investig, 2003 Ghazeeri, et al, Fertil Steril, 2003

46. Treatment Algorithms Path depends primarily on fertility desires Also depends on primary symptoms of patient

47. Desires Fertility The Problem: Anovulation The Solution: Reestablish Ovulation Question for patient: Willingness to wait? – Weight Loss – Insulin-sensitizers may take 3-5 months – Ovulation induction much quicker Harborne et al, The Lancet, April 8, 2003.

48. Weight Loss Modest weight loss (5%) can help – Lower androgen levels – Induce regular cycles Other health benefits for pregnancy – Diabetes – Hypertension

49. Metformin 5 weeks of treatment Ovulation rate of 34 % vs. 4% in placebo No ovulation – Given Clomiphene citrate – Increased ovulation rate to 90% Nestler et al, NEJM, 1998

50. Metformin and Pregnancy Pregnancy Class B PCOS increases risk of miscarriage – 30-50% higher Plaminogen activator inhibitor (PAI) – Causes placental insufficiency – Increases with increased insulin levels Kosasa, Contemporary OB/Gyn, March 2003

51. Metformin and Pregnancy Patients receiving 1.5g to 2.55g per day Decreased rate of miscarriage – From 73% to 10% Thought to be related to decrease PAI activity Glueck et al, Fertil Steril, 2001.

52. Metformin and Gestational Diabetes PCOS increases risk of GDM Metformin treatment decreases development of GDM – From 31% to 3% Further studies are warranted Glueck et al, Fertil Steril, 2002.

53. Ovulation Induction Clomiphene citrate – Can start at 50mg/day on days 5-9 – Up to 150mg/day Some sources up to 200mg/day in morbidly obese – Effective in about 85% of women with PCOS – Metformin-CC combination even more effective 90% in small study Further studies ongoing Stovall, OBG Management, June 2003

54. Other Induction Agents Human menopausal gonadotropin Follicle-stimulating hormone Referral to specialist

55. Fertility NOT Desired Regulate Cycles – Hormonal Contraception Oral Pills Patch Ring – Progesterone withdrawal Every 3 months Monthly

56. Hormonal Contraception Reduces gonadotropin stimulation on ovary Reduces androgen production Can help with hirsutism, acne Increase SHBG Use newer progestins – Desogestrel, Norgestimate

57. Caution Hormonal Contraception – Not as effective in morbidly obese – Increased risk of thrombotic event

58. Hirsutism - Treatment Reduce Androgens – Weight Loss – Hormonal Contraception – Anti-Androgens Mechanical Treatment – Shaving – Electrolysis – Laser

59. Hirsutism Treatment takes a long time Spironolactone – Binds to androgen receptor – Blocks 5α-Reductase – 25mg, 50mg,100mg, 200mg divided daily – Side effects Light-headedness, lethargy, menstrual irregularity, mastodynia

60. Spironolactone Use with contraception Theoretical risk of teratogenicity Minimize menstrual irregularity

61. Spironolactone Effectiveness – 40-88% reduction in diameter of hair growth – 6-12 months of use Futterweit, Obs and Gyn Survey, 1999.

62. Other Antiandrogens Flutamide – Blocks androgen binding to tissue – Rare fatal hepatotoxicity Finasteride – 5α-reductase inhibitor – 5mg/day – Don’t use in pregnancy – As effective as Spironolactone

63. Other treatments of hirsutism Eflornithine – Topical agent – Slows hair growth – Apply twice a day – Mechanical hair removal is required – Hair will reappear 2 months after stopping tx

64. Mechanical Treatment Can be used after medical treatment Laser – Most success in light skin, dark hair Electrolysis – Long-term treatments

65. Long-Term Consequences of PCOS Endometrial Cancer Coronary Risk

66. Endometrial Cancer Most common invasive gyn cancer Risks include – Unopposed estrogen – Obesity – High androstenedione levels – Risks that are common in PCOS patients

67. Decreasing Endometrial Risk Regulate menses Combination hormones Progesterone withdrawal

68. Coronary Risk Prediliction to Diabetes Dyslipidemia Obesity

69. Diabetes Risk Study of 122 obese women with PCOS Impaired Glucose Tolerance – 30-40% Type 2 Diabetes – 10% Ehrmann, et al., Diabetes Care, 1999.

70. Diabetes Risk What screening test? – Fasting Glucose – 75 gram GTT Risk of Diabetes with PCOS – 254 women with PCOS – 3.2% by fasting glucose alone – 7.5% with GTT Legro, et al, J Clin Endocrinol Metab, 2002.

71. Dyslipidemia Elevated Triglycerides Decreased HDL Increased LDL/HDL ratio

72. Overall Coronary Risk Hard to determine Studies have been poorly defined – Ovarian morphology – Oligomenorrhea Can be confounded by other known risk factors – Diabetes, Obesity

73. Long-Term Therapy Cyclic Estrogen/Progesterone – Reduces risk of endometrial hyperplasia and cancer Insulin-sensitizers – Uncertain of long-term benefit – May reduce risk of diabetes Need further studies

74. Take Home Treatment needs to be guided by patient desires and concerns Lifestyle modification Protect the endometrium