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Polycystic Ovary Syndrome: Characteristics and Clinical Controversies

Sponsored by ACCESS Medical Group Department of Continuing Medical Education Funded by an unrestricted educational grant from Abbott Laboratories. Polycystic Ovary Syndrome: Characteristics and Clinical Controversies. PCOS Overview, History, and Epidemiology.

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Polycystic Ovary Syndrome: Characteristics and Clinical Controversies

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  1. Sponsored by ACCESS Medical Group Department of Continuing Medical Education Funded by an unrestricted educational grant from Abbott Laboratories. Polycystic Ovary Syndrome: Characteristics and Clinical Controversies

  2. PCOS Overview, History, and Epidemiology

  3. Polycystic Ovarian Syndrome (PCOS)Overview • PCOS is a complex endocrine disorder affecting women of childbearing age characterized by increased androgen production and ovulatory dysfunction • PCOS is the leading cause of anovulatory infertility and hirsutism • Women with PCOS have an increased risk of miscarriage, insulin resistance, hyperlipidemia, type 2 diabetes, cardiovascular disease, and endometrial cancer Bauer J, et al. Epilepsy Res. 2000;41:163-167. Dunaif A, et al. Annu Rev Med. 2001;52:401-419. Franks S. N Engl J Med. 1995;333:853-861.

  4. PCOS and Stein-Leventhal Syndrome • PCOS was first identified by Stein and Leventhal in 1935 • They described a group of women who were obese and infertile, with enlarged ovaries with multiple cysts • Few of these original features are now considered consistent findings in PCOS Stein IF, Leventhal ML. Am J Obstet Gynecol. 1935;29:181-191. Dunaif A, et al. Annu Rev Med. 2001;54:401-419.

  5. Prevalence of PCOS in Various Populations of Women With oligomenorrhea* With amenorrhea* Unilateral temporolimbic epilepsy† Idiopathic generalized epilepsy‡ Primary generalized epilepsy† Reproductive-age (4% to 12%)§ Untreated epilepsy‡ Valproate-treated epilepsy‡ Carbamazepine-treated epilepsy‡ 0 15 30 45 60 75 90 Prevalence of PCOS, % *Franks s. N Engl J Med. 1995;333:853-861. †Herzog AG, et al. Epilepsia. 2001;42:311-315. ‡Duncan S. Epilepsia. 2001;42(suppl 3):60-65. §Dunaif A, et al. Annu Rev Med. 2001;52:401-419.

  6. PCOS Characteristics

  7. PCOS: National Institutes of Health Diagnostic Criteria • Presence of ovulatory dysfunction, polymenorrhea, oligomenorrhea, or amenorrhea • Clinical evidence of hyperandrogenism and/or hyperandrogenemia • Exclusion of other endocrinopathies (eg, Cushing syndrome, hypothyroidism, late-onset congenital adrenal hyperplasia Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

  8. Clinical Features of PCOSMenstrual Irregularity • May appear at puberty with a delayed menarche followed by the onset of irregular periods or as the breakdown of a previously regular cycle • Anovulation is usually chronic and presents as oligomenorrhea or amenorrhea Duncan S. Epilepsia. 2001;42(suppl 3):60-65. Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55. Lobo RA, et al. Ann Int Med. 2000;132:989-993.

  9. Clinical Features of PCOSHyperandrogenism • Symptoms may include hirsutism, acne, male pattern balding, and/or male distribution of body hair Acne Hirsutism Lobo RA, et al. Ann Intern Med. 2000;132:989-993.

  10. Common Endocrine Abnormalities in PCOS • Elevated luteinizing hormone (LH) • Increased LH/follicle-stimulating hormone (FSH) ratio • Elevated androgen levels • Decreased sex hormone binding globulin levels Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

  11. Metabolic Abnormalities in PCOS • Hyperinsulinemia and insulin resistance • Insulin resistance may be independent of the effect of obesity • Decreased peripheral insulin sensitivity and consequent hyperinsulinemia may play an important role in the pathogenesis of PCOS Franks S. N Engl J Med. 1995;333:853-861. Hopkinson ZE, et al. BMJ. 1998;317:329-332.

  12. Lipid and Lipoprotein Abnormalities in PCOS • Elevated LDL cholesterol • Elevated triglycerides • Decreased HDL cholesterol • Decreased apolipoprotein A-I • Impaired fibrinolytic activity Lobo RA, et al. Ann Int Med. 2000;132:989-993. Hopkinson ZE, et al. BMJ. 1998;317:329-332.

  13. Reproductive Sequelae of PCOS • PCOS is usually associated with varying degrees of infertility • It is a frequent cause of anovulatory infertility in women • The disorder often develops shortly after menarche, lasting for most of the reproductive life Legro RS. Mol Cell Endocrinol. 2002;186:219-225.

  14. PCOS Versus PCO

  15. Polycystic Ovaries (PCO) • 10 subcapsular follicular cysts, 2-8 mm in diameter, arranged around a thickened ovarian stroma • While associated with increased hirsutism, elevated testosterone, and irregular menstrual cycles, PCO are not intrinsically pathologic Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55.

  16. Polycystic OvariesNot Intrinsically Pathologic • PCO occur in about 17% to 22% of the general female population • As many as 25% of women with a radiographic finding of PCO have no endocrine or menstrual irregularities • An isolated finding of PCO may be a normal variation and does not necessarily imply altered fertility Ernst CL, et al. J Clin Psychiatry. 2002;63:(suppl 4):42-55. Genton P, et al. Epilepsia. 2001;42:295-304.

  17. Rates of PCOS and PCO in the General Population and Women With Epilepsy Polycystic Ovarian Syndrome Expert Consensus Panel 40 35 30 All premenopausal women 25 Prevalence, % 20 Women with epilepsy 15 10 5 0 PCOS PCO Genton P, et al. Epilepsia. 2001;42:295-304. Dunaif A, et al. Annu Rev Med. 2001;52:401-419. Herzog AG, et al. Epilepsia. 2001;42:311-315.

  18. Polycystic Ovarian Syndrome (PCOS) Versus Polycystic Ovaries (PCO) • PCOS: A metabolic disorder characterized by ovulatory dysfunction, hyperandrogenism, and exclusion of other endocrinopathies • PCO: The presence of multiple ovarian cysts 2-8 mm in diameter and increased ovarian stroma; this condition is not intrinsically pathologic Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

  19. Etiology of PCOS

  20. Theories of PCOS Development • PCOS may be caused by interactions between • Genetic factors (eg, autosomal dominant transmission) • Endocrine factors (eg, increased LH/FSH ratio, increased insulin and androgen concentrations) • Metabolic factors (eg, increased insulin resistance, decreased SHBG) • Neurologic factors (eg, epileptic discharges) • Environmental factors (eg, anabolic steroids) LH=luteinizing hormone; FSH=follicle stimulating hormone; SHBG=sex hormone binding globulin Herzog AG, et al. Epilepsia. 2001;42:311-315. Duncan S. Epilepsia. 2001; 42(suppl 3):60-65. Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55.

  21. Developmental Origin of PCOS • During gestation, human chorionic gonadotrophin, LH, and genes regulating folliculogenesis and steroidogenesis may cause excess prenatal androgen • Postpubertally, hyperinsulinemia and LH hypersecretion augment ovarian steroidogenesis, leading to anovulation Abbott DH, et al. J Endocrinol. 2002;174:1-5.

  22. Association Between Weight Gain and PCOS • Up to 50% of women with PCOS are moderately obese or overweight • Obesity is usually the android type, with increased waist-to-hip ratios • When present, obesity worsens insulin resistance and increases the risk for diabetes and cardiovascular disease Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55.

  23. Impaired Ovarian Function as a Cause of PCOS • PCOS may be caused by increased steroidogenic activity in the ovary • This increased activity may be a genetic defect in the ovary; the result is an ovary that secretes increased amounts of • Androstenedione (an androgen) • 17-hydroxyprogesterone (a steroid that is intermediate in the androgen pathway)

  24. Insulin Resistance and PCOS • Increased insulin levels can stimulate androgen production • Insulin can stimulate adrenal steroidogenesis by enhancing sensitivity to adrenocorticotrophic hormone and increasing pituitary LH release • Insulin-lowering therapies can restore menstrual cycles in some anovulatory women with PCOS • Defects in insulin receptors have been found in up to half of women with PCOS Dunaif A, et al. Annu Rev Med. 2001;52:401-419. Earnst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55.

  25. Polycystic Ovarian SyndromeGenetic Influences • Evidence suggests a defect in ovarian and androgen biosynthesis that may interact with an insulin abnormality • A familial aggregation of hyperandrogenism is found in first-degree relatives of women with PCOS • PCOS appears to have an autosomal dominant inheritance pattern Dunaif A, et al. Annu Rev Med. 2001;52:401-419. Franks S. N Engl J Med. 1995;333:853-861.

  26. Epilepsy and Reproductive Endocrine Dysfunction • Epileptic discharges may affect secretion of GnRH • Seizures can cause hyperprolactinemia, which can elevate LH levels and support androgenization • Epilepsy and PCOS may be caused by a common factor, such as a dysfunction in neurotransmission or genetic vulnerability Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55.

  27. Bipolar Disorder and Reproductive Endocrine Dysfunction • Women with bipolar disorder have a high prevalence of menstrual disturbances independent of therapeutic agent used • This finding may indicate compromise in reproductive endocrine function prior to treatment • It may represent a marker for an underlying hypothalamic-pituitary-gonadal axis dysregulation Rasgon NL, et al. J Clin Psychiatry. 2000;61:173-178.

  28. Women With Bipolar Disorder Have a High Rate of Menstrual Abnormalities In a study by Rasgon et al, • 59% of women treated for bipolar disorder had long menstrual periods • 18% displayed oligomenorrhea • These findings are consistent with a previous report that menstrual abnormalities are common in women with bipolar disorder receiving mood stabilizers Rasgon NL, et al. Bipolar Disord. (in press).

  29. Increased Insulin Resistance in Women With Bipolar Disorder • Insulin levels were measured in 42 women with bipolar disorder • Patients received at least 2 of the following: lithium, valproate, other anticonvulsants, or antipsychotics • 42% of women had insulin resistance • No difference was found in terms of which medication was used and the development of insulin resistance • Not clear if insulin resistance was due to treatment or bipolar disorder Rasgon NL, et al. Poster presented at the American Psychiatric Association annual meeting, Philadelphia, Pa, May 18-23, 2002.

  30. PCOSCharacteristics and Causes • A complex disorder characterized by increased androgen production and ovulatory dysfunction • The leading cause of anovulatory infertility • Different from polycystic ovaries (PCO), a condition that is not intrinsically pathologic • Caused by interactions between genetic, endocrine, metabolic, neurologic, and environmental factors

  31. Review of Clinical Data

  32. 100 90 80 70 60 50 40 30 20 10 0 Isojärvi et al 1993: Correlation Between AEDs and Menstrual Disturbances N=238 Menstrual Disturbances, % Carbam- azepine + Valproate Valproate Carbam- azepine Other AEDs AEDs=Antiepileptic drugs Isojärvi JIT, et al. N Engl J Med. 1993;329:1383-1388.

  33. 100 90 80 70 60 50 40 30 20 10 0 Isojärvi et al 1996: PCO, Hyperandrogenism, or Both From Valproate or Carbamazepine PCO, Hyperandrogenism, or Both, % Carbam- azepine Control Group Valproate Isojärvi JIT, et al. Ann Neurol. 1996;39:579-584.

  34. Isojärvi et al 1993 and 1996: Analysis • In both studies • None of the women taking valproate with PCO met the NIH criteria for PCOS • There is a lack of pretreatment data regarding ovarian structure and function • Designs were cross-sectional and retrospective Isojärvi JIT, et al. Ann Neurol. 1996;39:579-584. Ernst CL, et al. J Clin Psychiatry. 2002;63(suppl 4):42-55. Duncan S. Epilepsia. 2001;42(suppl 3):60-65.

  35. Isojärvi et al 1998: Testosterone and Insulin Levels After Switch From Valproate to Lamotrigine * 125 12 VPA=Valproate LTG=Lamotrigine 100 * 10 ‡ § § § 8 † 75 † Serum Testosterone, ng/dL Serum Insulin, mU/L 6 50 4 25 2 0 VPA Control VPA Control LTG 6 mo LTG 12 mo LTG 6 mo LTG 12 mo LTG 2 mo LTG 2 mo *P<.05 compared with control subjects. †P<.01 compared with valproate. ‡P<.05 compared with valproate. §P<.001 compared with valproate. Isojärvi JIT, et al. Ann Neurol. 1998;43:446-451.

  36. Isojärvi et al 1998: Analysis • The decline in the number of cysts after the switch from valproate to lamotrigine was not significantly significant • Only obese women on valproate were chosen for the study; it was not randomized • Only 12 women completed the study after 4 withdrew (25% dropout rate) • Criteria for patient selection were not provided; possible selection bias cannot be evaluated • Switching medications may increase the risk of seizures in a controlled patient Isojärvi JI, et al. Ann Neurol. 1998;43:446-451. Dean JC, et al. American Epilepsy Society Annual Meeting, 2001.

  37. Testosterone Concentrations in Women With Epilepsy Treated With Valproate or Lamotrigine 100 Clinically Significant Elevation (>70 ng/dL) 90 80 70 60 Testosterone Level, ng/dL 50 40 30 20 10 0 Lamotrigine Valproate Taylor A, et al. [Poster] American Psychiatric Association Annual Meeting. May, 2001.

  38. Taylor et al 2001: Analysis • Multicenter, international study (9 countries, 70 sites); 222 young women with epilepsy • Testosterone levels increased more in patients taking valproate, but both groups were well within normal range • Total cholesterol and LDL levels were lower in the valproate group • Insulin levels similar in both treatment groups Taylor A, et al. [Poster] American Psychiatric Association Annual Meeting. May, 2001.

  39. Untreated Valproate Carbamazepine Polytherapy (0%) No Association Found Between PCOS and Valproate or Carbamazepine Therapy Incidence of PCOS, % Treatment Bauer J, et al. Epilepsy Res. 2000;41:163-167.

  40. Bauer et al 2000: Analysis • Using NIH criteria for PCOS, investigators found no relationship between the administration of valproate, carbamazepine, or no treatment and the development of PCOS • Investigators concluded the study suggests manifestations of PCOS in women with focal epilepsy are not related to the administration of valproate or carbamazepine Bauer J, et al. Epilepsy Res. 2000;41:163-167.

  41. Reproductive Endocrine Disorders in Epilepsy Not Associated With AEDs 100 Therapy 90 including 80 valproate 70 Therapy not 60 Women With a Reproductive Endocrine Disorder, % including 50 valproate 40 30 Untreated 20 10 0 PCOS PCO Elevated Androgens Irregular Menstrual Cycles Bilo L, et al. J Clin Endocrinol Metab. 2001;86:2950-2956.

  42. Bilo et al 2001: Analysis • In a study of women with epilepsy, no significant association was found between epilepsy type, AED used (valproate or other), and the development of reproductive endocrine disorders • Conclusion: the prevalence of disordered ovulation—especially PCOS—is increased in epilepsy, independent of AED use or type of seizure disorder Bilo L, et al. J Clin Endocrinol Metab. 2001;86:2950-2956.

  43. 100 90 80 70 60 50 40 30 20 10 0 Valproate Not Associated With Increased Menstrual Disorders, PCO, or Both Valproate Other AEDs Rate, % Menstrual Disturbances Menstrual Disturbances and PCO PCO PCOS *Other AEDs: carbamazepine, lamotrigine, primidone. Luef G, et al. Epilepsy Res. 2002;48:91-102.

  44. Luef et al 2002: Analysis • Investigators noted that, in contrast with the studies of Isojärvi et al, they found no increased frequency of menstrual disorders in women receiving valproate (n=22) compared with women receiving carbamazepine or lamotrigine (n=21) after at least 2 years of treatment • A limitation of this study was its use of a small sample size and the cross-sectional study design Luef G, et al. Epilepsy Res. 2002;48:91-102.

  45. Larger Study Reaffirms No Association Between Valproate and PCO 100 N=105 90 80 Valproate 70 60 Carbamazepine Incidence, % 50 40 30 20 10 0 Menstrual Disturbances PCO Luef G, et al. J Neurol. 2002;249:835-841.

  46. Luef et al 2002:Analysis of Larger Study • Investigators did not find an increase in menstrual disturbances or of the incidence of PCO in women with epilepsy treated with valproate (n=52) compared with women with epilepsy treated with carbamazepine (n=53) • The rate of PCO incidence in this study of women with epilepsy (27%) was comparable to the rate of PCO incidence in the general population (20%-30%) Luef G, et al. J Neurol. 2002;835-841.

  47. Women With Bipolar Disorder: No PCOS-Like Changes With Lithium or Divalproex Treatment Measurement Normal Range Li DVP Li + DPV T, ng/dL 20-80 19.8 26.2 26.4 Bio T, ng/dL <5 3.3 4.5 5.4 DHEA, ng/dL 0.8-10.5 6.3 4.9 2.2 LH, mIU/mL 1.0-18.5 6.5 5.7 6.6 FSH, mIU/mL 2.5-8.0 6.9 4.9 4.5 Bio T=Bioavailable testosterone; DHEA =Dehydroepiandrosterone; DVP=Divalproex sodium; FSH=Follicle stimulating hormone; Li=Lithium; LH=Luteinizing hormone; T=Testosterone Rasgon NL, et al. J Clin Psychiatry. 2000;61:173-178.

  48. Rasgon et al 2000: Analysis • Women with bipolar disorder received divalproex (n=10), lithium (n=10), or both drugs (n=2) • At the beginning of the study, none of the women met the criteria for PCOS • All women were treated for >12 months; none developed PCOS • Women in the study reported high rates of menstrual disturbances, independent of therapeutic agent used, suggesting they may have had a compromised hypothalamic-pituitary-gonadal axis Rasgon NL, et al. J Clin Psychiatry. 2000;61:173-178.

  49. Association of Epilepsy Type, AED, and Ovulatory Function • Investigators studied the association of epilepsy syndrome category and AED (carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine, or gabapentin) on ovulatory function • There was no association between AED used and anovulatory cycles; however, women with IGE who were taking or who had taken valproate within the last 3 years were at the highest risk for anovulatory cycles • There was no difference in rate of PCO by AED Morrell MJ, et al. Ann Neurol. (In press).

  50. Morrell et al 2002: Analysis • The effects of the epilepsy syndrome could not be separated from the effects of AEDs; AED use was guided to some extent by the epilepsy syndrome • The study did not control for past AED exposure; a study of newly diagnosed women with epilepsy receiving AEDs de novo is needed to define drug effects Morrell MJ, et al. Ann Neurol. (In press).

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