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.
PCOS Overview, History, and Epidemiology
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.
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.
Prevalence of PCOS in Various Populations of Women 0 15 30 45 60 75 90 Reproductive-age (4% to 12%) § Primary generalized epilepsy † Carbamazepine-treated epilepsy ‡ Untreated epilepsy ‡ Valproate-treated epilepsy ‡ Idiopathic generalized epilepsy ‡ Unilateral temporolimbic epilepsy † With amenorrhea* With oligomenorrhea* 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.
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.
Clinical Features of PCOS Menstrual 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 .
Clinical Features of PCOS Hyperandrogenism
Symptoms may include hirsutism, acne, male pattern balding, and/or male distribution of body hair
Lobo RA, et al. Ann Intern Med . 2000;132:989-993. Hirsutism Acne
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.
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.
Lipid and Lipoprotein Abnormalities in PCOS
Elevated LDL cholesterol
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.
Reproductive Sequelae of PCOS Legro RS. Mol Cell Endocrinol. 2002;186:219-225.
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
PCOS Versus PCO
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.
Polycystic Ovaries Not 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.
Rates of PCOS and PCO in the General Population and Women With Epilepsy 0 5 10 15 20 25 30 35 40 PCO PCOS All premenopausal women Women with epilepsy Prevalence, % 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. Polycystic Ovarian Syndrome Expert Consensus Panel
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
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. LH=luteinizing hormone; FSH=follicle stimulating hormone; SHBG=sex hormone binding globulin
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.
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.
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)
Insulin Resistance and 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.
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
Polycystic Ovarian Syndrome Genetic Influences Dunaif A, et al. Annu Rev Med . 2001;52:401-419. Franks S. N Engl J Med . 1995;333:853-861.
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
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.
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.
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).
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.
PCOS Characteristics 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
Review of Clinical Data
Isojärvi et al 1993: Correlation Between AEDs and Menstrual Disturbances Isojärvi JIT, et al. N Engl J Med . 1993;329:1383-1388. N=238 Valproate Carbam- azepine Other AEDs Carbam- azepine + Valproate Menstrual Disturbances, % AEDs=Antiepileptic drugs 0 10 20 30 40 50 60 70 80 90 100
Isojärvi et al 1996: PCO, Hyperandrogenism, or Both From Valproate or Carbamazepine Isojärvi JIT, et al. Ann Neurol . 1996;39:579-584. PCO, Hyperandrogenism, or Both, % Valproate Carbam- azepine Control Group 0 10 20 30 40 50 60 70 80 90 100
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.
Isojärvi et al 1998: Testosterone and Insulin Levels After Switch From Valproate to Lamotrigine Isojärvi JIT, et al. Ann Neurol . 1998;43:446-451. 0 2 4 6 8 10 12 VPA LTG 6 mo Control LTG 12 mo LTG 2 mo 50 100 Serum Testosterone, ng/dL Serum Insulin, mU/L 25 75 125 VPA LTG 6 mo Control LTG 12 mo LTG 2 mo VPA=Valproate LTG=Lamotrigine * * * P <.05 compared with control subjects. † P <.01 compared with valproate. ‡ P <.05 compared with valproate. § P <.001 compared with valproate. † ‡ † § § §
Isojärvi et al 1998: Analysis Isojärvi JI, et al. Ann Neurol . 1998;43:446-451. Dean JC, et al. American Epilepsy Society Annual Meeting, 2001.
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
Testosterone Concentrations in Women With Epilepsy Treated With Valproate or Lamotrigine Taylor A, et al. [Poster] American Psychiatric Association Annual Meeting. May, 2001. Clinically Significant Elevation (>70 ng/dL) Testosterone Level, ng/dL 0 10 20 30 40 50 60 70 80 90 100 Lamotrigine Valproate
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.
No Association Found Between PCOS and Valproate or Carbamazepine Therapy Bauer J, et al. Epilepsy Res . 2000;41:163-167. Incidence of PCOS, % Treatment Untreated Valproate Carbamazepine Polytherapy (0%)
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.
Reproductive Endocrine Disorders in Epilepsy Not Associated With AEDs Bilo L, et al. J Clin Endocrinol Metab . 2001;86:2950-2956. Women With a Reproductive Endocrine Disorder, % 0 10 20 30 40 50 60 70 80 90 100 PCOS Elevated Androgens Therapy including valproate Therapy not including valproate Untreated PCO Irregular Menstrual Cycles
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.
Valproate Not Associated With Increased Menstrual Disorders, PCO, or Both Luef G, et al. Epilepsy Res . 2002;48:91-102. *Other AEDs: carbamazepine, lamotrigine, primidone. Menstrual Disturbances PCO Menstrual Disturbances and PCO PCOS Valproate Other AEDs Rate, % 0 10 20 30 40 50 60 70 80 90 100
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.
Larger Study Reaffirms No Association Between Valproate and PCO Luef G, et al. J Neurol . 2002;249:835-841. N=105 0 10 20 30 40 50 60 70 80 90 100 Menstrual Disturbances PCO Valproate Carbamazepine Incidence, %
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.
Women With Bipolar Disorder: No PCOS-Like Changes With Lithium or Divalproex Treatment Rasgon NL, et al. J Clin Psychiatry . 2000;61:173-178. 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 et al 2000: Analysis Rasgon NL, et al. J Clin Psychiatry . 2000;61:173-178.
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
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).
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).
Menstrual Abnormalities in Women With Bipolar Disorder 0 5 10 15 20 25 30 35 40 45 50 Valproate No Valproate Controls (0%) O’Donovan C, et al. J Clin Psychiatry . 2002;63:322-330. Incidence, %
O’Donovan et al 2002: Analysis
The data may have been distorted because the study relied on a mailed questionnaire that asked women to remember menstrual abnormalities in the past (recall bias)
Another major limitation of the study was that a large number of women did not answer the study questionnaires (participation bias)
O’Donovan C, et al. J Clin Psychiatry . 2002;63:322-330.
Long-Term Valproate Use in Rhesus Monkeys: No Effect on Testosterone or LH Levels 0 10 20 30 40 50 60 70 80 90 100 Control 1st Trimester 2nd Trimester Last Trimester Total Testosterone Luteinizing Hormone Total Testosterone, ng/dL Luteinizing Hormone, ng/mL 0 0.5 1.0 1.5 2.0 Valproate Treatment Ferin M, et al. Poster presented at the American Epilepsy Society annual meeting; Seattle, Washington; December 6-11, 2002.
Long-Term Valproate Use in Rhesus Monkeys: Glucose Tolerance Test 200 150 100 50 0 Valproate Control Dextrose 0.1 g/kg 200 150 100 50 0 • • • Glucose and insulin responses to glucose tolerance test the same in control and valproate-treated monkeys • • • • • • • • -5 Minutes 0 5 10 15 20 25 30 35 -5 Minutes 0 5 10 15 20 25 30 35 • • Ferin M, et al. Poster presented at the American Epilepsy Society annual meeting; Seattle, Washington; December 6-11, 2002. Glucose, ng/dL Insulin, U/mL
Ferin et al 2002: Analysis Ferin M, et al. Poster presented at the American Epilepsy Society annual meeting; Seattle, Washington; December 6-11, 2002.
Long-term treatment (12-15 months) with valproate in monkeys was not associated with differences in testosterone or LH levels compared with a control group; both groups also had similar glucose and insulin responses to a glucose tolerance test
Examination of all 14 ovaries in valproate-treated monkeys showed no histological evidence of PCOS
The investigators concluded: “These results do not support the hypothesis that treatment with valproate per se is responsible for the induction of PCOS”
Summary of Literature on PCOS and Valproate Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55. Genton P, et al. Epilepsia . 2001;42:295-304. Dean JC, et al. [Poster] American Epilepsy Society Annual Meeting, 2001.
There are no reliable data showing a greater prevalence of PCOS in women taking valproate
A careful analysis of Isojärvi’s findings shows that none of the women in key studies met the NIH criteria for PCOS
Valproate remains a first-line option for the treatment of women with epilepsy or bipolar disorder
Switching patients with epilepsy who are adequately controlled with valproate must be exercised with extreme caution
Proper Management of Patients With PCOS and Epilepsy
PCOS in Women With Epilepsy Management Goals
For reproductive endocrine disorders
Hyperandrogenism: hair removal, antiandrogens
Anovulation: clomiphene, gonadotropins
For metabolic and cardiovascular disease
Insulin resistance: insulin sensitizing agents
Elevated triglycerides and LDL, decreased HDL: statins and fibrates
Obesity: calorie restriction
Lobo RA, et al. Ann Int Med . 2000;132:989-993. Franks S. N Engl J Med . 1995;333:853-861.
Failure to Control Seizures After Switch From Valproate to Lamotrigine Dean JC, et al. Poster presented at American Epilepsy Society Annual Meeting, 2001. 0 10 20 30 40 50 60 70 80 90 100 JME GTCS ABS MJ Seizures controlled with valproate Seizures controlled with lamotrigine after switch Seizure Control , % JME=juvenile myoclonic epilepsy; GTCS=generalized tonic-clonic seizures; ABS=absence seizures; MJ= myoclonic jerks
Effects of Antiepileptic Drugs on Oral Contraception Efficacy Morrell MJ. Neurology . 1998;51(suppl 4):S21-S27. Hachad H, et al. Ther Drug Monit. 2002;24:91-103. Reduces Efficacy No Effect on Efficacy Barbiturates Felbamate Carbamazepine Gabapentin Phenytoin Lamotrigine Tiagabine Valproate Topiramate Oxcarbazepine
PCOS is a serious reproductive endocrine disorder characterized by ovulatory dysfunction and hyperandrogenism
It needs to be distinguished from PCO, a condition that is not intrinsically pathologic
There are no reliable data showing a greater prevalence of PCOS in women treated with valproate or any AED
Treatment choices should be based on the most effective agent for controlling symptoms