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  • Polycystic Ovarian Syndrome (PCOS). Overview. Polycystic ovarian syndrome is a complex endocrine disorder affecting women in their reproductive years. 1 It is characterized by increased androgen production and disordered gonadotropin secretion, which results in chronic anovulation. 2 It is the leading cause of anovulatory infertility and hirsutism. 2,3 PCOS is also associated with disorders of reproduction, metabolism, and general health, including increased risk of miscarriage, insulin resistance, hyperlipidemia, cardiovascular disease, and endometrial cancer. 1 Obesity is common but not universal in women with PCOS. 3 Women with PCOS have high rate of type 2 diabetes; these women have hyperlipidemia and a greatly increased risk of cardiovascular disease. 3 References 1. Bauer J, et al. Epilepsy Res . 2000;41:163-167. 2. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 3. Franks S. N Engl J Med . 1995;333:853-861.
  • PCOS and Stein-Leventhal Syndrome. PCOS was first recognized by Stein and Leventhal, 2 American gynecologists, who published a paper in 1935 describing a group of women who were obese, had severe menstrual irregularities, and were infertile. 1,2 At laparatomy, the women were found to have enlarge ovaries with multiple large cysts. Later investigators determined that such women have elevated testosterone and luteinizing hormone (LH) levels. The concept of PCOS has evolved to include these endocrine findings and is associated with obesity, hirsutism, and infertility. It was also determined that women with PCOS were at increased risk of endometrial carcinoma (as a result of annovulation) and of early development of diabetes and atherosclerotic disease. It is interesting to note that few of the original features identified by Stein and Leventhal are consistent findings in PCOS. 3 For example, women with PCOS can be lean, and symptoms of androgen excess, such as hirsutism, may be absent because of individual variations in target-tissue sensitivity. References 1. Betts T, et al. Seizure . 2001;10:220-228. 2. Stein IF, Leventhal ML. Am J Obstet Gynecol . 1935:29:181-191. 3. Dunaif A, et al. Annu Rev Med . 2001;52:401-419.
  • Prevalence of PCOS in Various Populations of Women. The prevalence of PCOS among reproductive-age women has been estimated at 4% to 12%. 1 Bauer studied 93 women with epilepsy and found that the incidence of PCOS was 10.5% in an untreated group, 11.1% in a valproate-treated group, and 10% in a carbamazepine-treated group. 2 A study of women undergoing electrolysis in Alabama found that 12% had PCOS. 1 Bilo et al reported that 15% of 20 women with idiopathic generalized epilepsy had PCOS. 2 Herzog et al found 22.2% of 36 women with unilateral temporolimbic epilepsy had PCOS. 3 In a study from England, 37% of women with amenorrhea and 90% of women with oligomenorrhea had PCOS. 4 References 1. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 3. Herzog AG, et al. Epilepsia . 2001;42:311-315. 4. Franks S. N Engl J Med . 1995;333:853-861.
  • PCOS: National Institutes of Health Diagnostic Criteria. In the United States, PCOS is defined with diagnostic criteria developed by the National Institutes of Health (NIH) as an ovulatory dysfunction with clinical evidence of hyperandrogenism and/or hyperandrogenemia. 1,2 For the condition to be diagnosed, related disorders, such as those that affect adrenal or thyroid function (eg, androgen-secreting neoplasms), must be excluded. 1,3,4 The diagnosis of PCOS is generally made through a combination of clinical, ultrasonographic, and biochemical criteria. 4 This definition excludes the finding of polycystic ovaries (PCO), multifollicular ovaries, or hyperandrogenism in isolation. Outside of the United States, the diagnosis is usually based on ovarian morphology, and affected women may be further subgrouped by ovulatory status. Because the anovulatory subgroup may demonstrate more profound insulin resistance, differences in diagnostic criteria may explain many of the divergent findings between US and European studies of patients with this disorder. 1 References 1. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 3. Bauer J, et al. Epilepsy Res . 2000;41:163-167. 4. Chappell KA, et al. Ann Pharmacother . 1999;33:1211-1216.
  • Clinical Features of PCOS. Menstrual Irregularity. PCOS is a disorder characterized by menstrual irregularity and hyperandrogenemia. Menstrual irregularity: This problem may manifest itself at puberty with a delayed menarche followed by the onset of irregular periods or as the breakdown of a previously regular cycle within a few years and is often associated with weight gain. 1 Anovulation in PCOS is usually chronic and presents as oligomenorrhea or amenorrhea around the time of the onset of menstruation. 2 It has been reported that 50% of women with PCOS are obese, and 20% of these obese women will have either impaired glucose tolerance or type 2 diabetes by the age of 40 years. 1 Other conditions associated with PCOS include infertility, endometrial hyperplasia or malignancy, hypertension, coronary artery disease, and adverse lipid profiles. 3 References 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 2. Lobo RA, et al. Ann Int Med . 2000;132:989-993. 3. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55.
  • Clinical Features of PCOS. Hyperandrogenism. Hyperandrogenemia is a key feature of PCOS, and it may appear as hirsutism, acne, male pattern balding, and/or male distribution of body hair. 1 Reference 1. Lobo RA, et al. Ann Intern Med . 2000;132:989-993.
  • Common Endocrine Abnormalities in PCOS. A number of endocrine abnormalities are common in many women with PCOS, but none is pathognomonic or found in all women with the disorder. 1 These abnormal findings include: Elevated LH level in urine and serum Increased LH/follicle-stimulating hormone (FSH) ratio Elevated androgen levels In general, estrogens and FSH remain in the normal range, while sex hormone binding globulin (SHBG) is lower than normal, which may increase free testosterone levels. Women with PCOS tend to be hyperinsulinemic, regardless of whether they are lean or obese, compared with normal women. Reference 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65.
  • Metabolic Abnormalities in PCOS. Women with PCOS have a greater frequency and degree of both hyperinsulinemia and insulin-resistance than weight-matched controls. 1 Insulin resistance is independent of the effect of obesity—both lean and obese women with PCOS demonstrate decreased insulin sensitivity, although insulin resistance is more pronounced in women with both obesity and PCOS. 1 Insulin resistance has been found to be more pronounced in women with chronic anovulation than in those who have ovulatory cycles. 2 In women with PCOS, insulin resistance is characterized by decreased sensitivity to insulin in peripheral tissues but not hepatic resistance, unlike insulin resistance in type 2 diabetes. There is evidence to support the hypothesis that decreased peripheral insulin sensitivity and consequent hyperinsulinemia are pivotal to the pathogenesis of PCOS. 3 Insulin acts in the liver to inhibit the production of SHBG and insulin-like growth factor 1 (IGF-1) binding protein. A reduction in SHBG leads to an increase in free testosterone. 3 Therefore, insulin resistance not only increases the secretion of ovarian androgen but also promotes an increase in the proportion of free (biologically active) hormone. References 1. Franks S. N Engl J Med . 1995;333:853-861. 2. Lobo RA, et al. Ann Int Med . 2000;132:989-993. 3. Hopkinson ZE, et al. BMJ . 1998;317:329-332.
  • Lipid and Lipoprotein Abnormalities in PCOS. Women with PCOS have many abnormalities in lipid and lipoprotein profiles, including elevated levels of triglycerides, and low-density lipoprotein (LDL) cholesterol and low levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I. 1 Reports cite the most characteristic lipid abnormality in women with PCOS to be decreased levels of HDL 2 . The combination of elevated triglycerides and decreased HDL is strongly linked with cardiovascular disease. 2 Some authors recommend that HDL cholesterol be measured during routine cholesterol screening in women with PCOS. 1 Another common finding in women with PCOS is impaired fibrinolytic activity, as assessed by measurements of elevated levels of circulating plasminogen activator inhibitor levels, a potent inhibitor of fibrinolysis. Elevated levels of plasminogen activator inhibitor have been shown to predict the occurrence of myocardial infarction. 2 References 1. Lobo RA, et al. Ann Int Med . 2000;132:989-993. 2. Hopkinson ZE, et al. BMJ . 1998;317:329-332.
  • Reproductive Sequelae of PCOS. Polycystic ovarian syndrome tends to develop shortly after menarche and continues for most of the reproductive life. 1 It may also appear as a breakdown of a previously regular menstrual cycle, which is often associated with weight gain. 2 Approximately 50% of women with PCOS are obese. A major concern with PCOS is infertility. In large studies of of anovulatory infertile women, PCOS has consistently been identified as the cause of infertility in 75% of cases. 1 When women with PCOS attempt to become pregnant through ovulation induction, they are at increased risk of multiple pregnancies. Women with PCOS receiving in vitro fertilization have multiple pregnancy rates substantially higher than women with other diagnoses. 1 References 1. Legro RS. Mol Cell Endocrinol . 2002;186:219-225. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65.
  • Polycystic Ovaries (PCO). A polycystic ovary is radiographically diagnosed by pelvic ultrasound and is defined as the presence of at least 10 subcapsular follicular cysts, measuring 2 to 8 mm in diameter, arranged around or within thickened ovarian stroma. 1 It has been estimated that PCO appear in 17% to 22% of the general population. It is important to note the PCO is not an intrinsically pathologic condition, and up to 25% of women with PCO have no endocrine or menstrual irregularities. 1 However, some investigators, such as Farquhar et al, have found that hirsutism, elevated testosterone levels, and irregular menstrual cycles were significantly more frequent among women with PCO. 2 References 1. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55. 2. Farquhar CM, et al. Aust N Z J Obstet Gynaecol . 1994;34:67-72.
  • Polycystic Ovaries. Not Intrinsically Pathologic. Polycystic ovaries are a common finding in the female population. Estimations have varied, but PCO seems to occur in about 17% to 22% of the general population. 1 Few women with PCO have fully developed PCOS. 2 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. 2 It is important to distinguish between PCO and PCOS when interpreting clinical studies. 1 PCO is not intrinsically pathologic. 1 References 1. Ernst CL, et al. J Clin Psychiatry . 2002;63:(suppl 4):42-55. 2. Genton P, et al. Epilepsia . 2001;42:295-304.
  • Rates of PCO and PCOS in the General Population and Women With Epilepsy. An expert consensus panel convened on June 10, 2002 to review issues pertaining to polycystic ovarian syndrome and women with epilepsy and bipolar disorder. The panel reported that polycystic ovaries are found in as many as 22% of the general premenopausal female population, 1 compared with up to 38% of women with epilepsy. They said that PCOS has been reported in up to 12% of the general premenopausal female population and in up to 25% of women with epilepsy. 2,3 Members of the Polycystic Ovarian Syndrome Expert Panel: Andrea E. Dunaif, MD, Northwestern University Feinberg School of Medicine, Chicago, Illinois. David A. Ehrmann, MD, the University of Chicago, Chicago, Illinois. Andrew G. Herzog, MD, Beth Israel Deaconess Medical Center, Wellesley, Massachusetts. Richard S. Legro, MD, Hershey Medical Center, Hershey, Pennsylvania. Natalie L. Rasgon, MD, PhD, UCLA School of Medicine, Los Angeles, California. References 1. Genton P, et al. Epilepsia . 2001;42:295-304. 2. Herzog AG, et al. Epilepsia . 2001;42:311-315. 3. Dunaif A, et al. Annu Rev Med . 2001;52:401-419.
  • Polycystic Ovarian Syndrome (PCOS) Versus Polycystic Ovaries (PCO). It is important to distinguish between polycystic ovaries (PCO) and polycystic ovarian syndrome (PCOS). PCO is frequently defined by ultrasonographic and anatomic criteria as the presence of multiple ovarian cysts 2 to 8 mm in diameter and increased ovarian stroma and/or size. 1 As noted earlier, PCO is not intrinsically pathologic. 2 The definition of PCOS differs in the United States and Europe: In the United States, PCOS is defined as a metabolic syndrome, and anatomic changes need not be present for diagnosis. In Europe, PCOS generally is defined as PCO in the presence of 1 or more clinical signs of endocrine dysfunction, such as menstrual irregularity, hirsutism, or infertility. An NIH consensus conference on PCOS specified 3 criteria for diagnosing the disorder 1 : (1) presence of ovulatory dysfunction, polymenorrhea, oligomenorrhea, or amenorrhea; (2) clinical evidence of hyperandrogenism or hyperandrogenemia; and (3) exclusion of other endocrinopathies (eg, Cushing syndrome, hypothyroidism, or late-onset congenital adrenal hyperplasia). Anatomical evidence of subcapsular cysts (eg, by ultrasonagraphy) is not considered a diagnostic criterion for PCOS by the NIH. 2 References 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 2. Ernst CL, et al. J Clin Psychiatry . 2002;63:(suppl 4):42-55.
  • Theories of PCOS Development. There are several hypotheses concerning the etiology of PCOS. It is a syndrome that may have several etiologies and contributing factors. 1 These may be genetic, endocrine, metabolic, neurologic, and environmental factors. 1,2 Genetic. Various modes of transmission have been suggested, including autosomal dominant. 3 Endocrine. Possible endocrine factors that may contribute to the development of PCOS include an increased LH/FSH ratio and increased insulin and androgen concentrations. Increased 17-hydroxyprogesterone levels in thecal cells may play a role in the development of PCOS. Metabolic. Insulin resistance decreases the release of SHBG in the liver, which increases free androgen levels. 2 Neurologic. The epileptic discharges from the amygdala to the hippocampus that affect the secretion of gonadotrophin-releasing hormone (GnRH) may contribute to PCOS development in epilepsy. 3 Environmental. Drugs, such as anabolic steroids and antiepileptic drugs (AEDs), have been implicated in the development of PCOS. References 1. Herzog AG, et al. Epilepsia . 2001;42:311-315. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 3. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55.
  • Developmental Origin of PCOS. Abbott et al have proposed a developmental origin of PCOS. According to their view, during gestation, placental human chorionic gonadotrophin (hCG), fetal pituitary LH, and genes regulating folliculogenesis and steroidogenesis, individually or together, result in fetal ovarian hyperandrogenemia that leads to prenatal, and possibly prepubertal, exposure to excess androgen. 1 Postpubertally, this early exposure to excess androgen diminishes steroid hormone negative feedback on pituitary LH, resulting in abnormal LH secretion and predisposing women to accumulation of abdominal (central) adiposity that exaggerates insulin resistance. The resulting hyperinsulinemia interacts with LH hypersecretion to augment ovarian steroidogenesis and induce premature arrest of the follicle development and anovulation. Reference 1. Abbott DH, et al. J Endocrinol . 2002;174:1-5.
  • Association Between Weight Gain and PCOS. Obesity has been associated with menstrual cycle abnormalities by many authors. 1 For example, Hartz et al found a significantly higher prevalence of anovulation, oligomenorrhea, and hirsutism in obese women than in normal-weight women. 2 It has been observed that up to 50% of women with PCOS are moderately obese or overweight to some degree. Obesity is associated with decreased levels of SHBG and elevated levels of estrogen. 1 Obesity may promote PCOS through such mechanisms as increased peripheral aromatization of androgen to estrogen within adipose tissue and consequent sensitization of gonadotropins by constant acyclic estrogen feedback. Also, decreased levels of SHBG associated with obesity may produce increased relative levels of free serum testosterone. 1 The obesity in women with PCOS is usually the android type, with increased waist-to-hip ratios. 3 When present, obesity worsens insulin resistance and increases the risk for diabetes and cardiovascular disease. The treatment of obesity should be a major focus of preventive health care for women with PCOS. References 1. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55. 2. Hartz AJ, et al. Int J Obes . 1979;3:57-73. 3. Lobo RA, et al. Ann Int Med . 2000;132:989-993.
  • Impaired Ovarian Function as a Cause of PCOS. Studies focusing on women with PCOS suggest that the disorder may be caused by increased steroidogenic activity that is an intrinsic, presumably genetic, defect in the ovary. 1 In vitro studies show that women with PCOS secrete increased amounts of androstenedione (an androgen) and 17-hydroxyprogesterone (a steroid that is an intermediate in the androgen and glucocorticoid biosynthetic pathway) from thecal cells (the androgen-producing cells of the ovary). 1 This increased secretion by thecal cells may be a result of dysregulation of the rate-limiting enzyme in androgen biosynthesis, cytochrome P-450c17  . 2 References 1. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 2. Franks S. N Engl J Med . 1995;333:853-861.
  • Insulin Resistance and PCOS. Several findings suggest that insulin resistance plays an important role in the pathogenesis of anovulation in women with PCOS. Research has shown that experimentally raising insulin levels can directly stimulate ovarian androgen production in women with PCOS. 1 Results from similar studies suggest that insulin can stimulate adrenal steroidogenesis by enhancing sensitivity to adrenocorticotrophic hormone (ACTH) and can increase pituitary LH release. 1 These reproductive effects of insulin appear to be limited to women with PCOS. Another significant finding is that insulin-lowering therapies can restore ovulatory menstrual cycles in some chronically anovulatory women with PCOS. 1 A genetic defect may be responsible for the insulin resistance found in women with PCOS. 2 Defects in insulin receptors have been reported in up to half of women with PCOS; also a decrease in tyrosine phosphorylation and an increase in serine phosphorylation, which all contribute to impaired insulin activity. There is also evidence that dysfunction of  -cells (responsible for pancreatic insulin production) is also evident among women with PCOS. 2 Women with PCOS also have a higher incidence of impaired glucose tolerance (31%-35% versus 7.8%) and undiagnosed type 2 diabetes (7.5%-10% versus 1%) compared with the general US female population. References 1. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 2. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55.
  • Polycystic Ovarian Syndrome. Genetic Influences. A genetic basis for PCOS appears to be likely, with increasing evidence pointing to a genetic defect in ovarian and adrenal androgen biosynthesis that may interact with an insulin abnormality. 1,2 Investigators report familial aggregation of hyperandrogenism in first-degree relatives of patients with PCOS, consistent with an autosomal dominant inheritance pattern. Familial clustering of PCOS has been documented and is consistent with a genetic susceptibility to the disorder. 1 In addition, brothers of women with PCOS often show evidence of insulin resistance and elevated dehydroepiandrosterone levels, findings that suggest their reproductive and metabolic phenotype resembles that of their sisters with PCOS. 1 References 1. Dunaif A, et al. Annu Rev Med . 2001;52:401-419. 2. Franks S. N Engl J Med . 1995;333:853-861.
  • Epilepsy and Reproductive Endocrine Dysfunction. Some investigators have suggested that epilepsy may play a role in the development of PCOS. PCOS has been reported to occur in 20% of women in one group with temporal lobe epilepsy and 25% of 20 women with complex partial seizures, most of whom were unmedicated. 1 Another investigator reported PCOS in 15% of 20 women with primary generalized epilepsy. In general, it has been reported that PCOS occurs in 13% to 25% of women with epilepsy. 2 Several factors could explain epilepsy’s role in the development of PCOS in women with epilepsy 1 : Epileptic discharges from the amygdala to the hippocampus may affect the secretion of GnRH, a hypothalamic hormone that controls the cyclic release and concentration of the pituitary gonadotrophins FSH and LH, and may induce the development of PCOS. Anovulatory cycles can trigger limbic seizure discharges, which can reduce serum dopamine levels, in turn producing hyperprolactinemia, which can promote elevated levels of LH that lead to androgenization. It is also possible that both epilepsy and reproductive endocrine disorders might be caused by a common dysfunction in neurotransmission or genetic vulnerability. References 1. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55. 2. Herzog AG, et al. Epilepsia . 2001;42:311-315.
  • Bipolar Disorder and Reproductive Endocrine Dysfunction. In Rasgon et al, 1 PCOS-like changes were not observed in women with bipolar disorder treated with either divalproex or lithium monotherapy. However, 18 out of the 22 subjects reported some type of menstrual dysfunction. Four of the 18 subjects had menstrual dysfunction that preceded the diagnosis of bipolar disorder. The high rate of reported menstrual disturbances may indicate a preexisting compromise in reproductive endocrine function in women with bipolar disorder. This potential compromise, in turn, may be a marker for dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis. Dysregulation of the HPG axis may be a possibility because dysregulation of the hypothalamic-pituitary adrenal and hypothalamic-pituitary-thyroid axes has been found in many cases of women with bipolar disorder. Reference 1. 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, 1 data on 17 women with bipolar disorder were collected. All women received medications for bipolar disorder, and 35% of the women received oral contraceptives. The investigators reported that long menstrual cycles were present in 59% of patients, including those who were receiving oral contraceptives. Of these patients, 18% had oligomenorrhea. This finding was consistent with an earlier report by the same authors that menstrual abnormalities are common in women with bipolar disorder who receive mood stabilizers. Although it is possible that long menstrual cycles resulted from the pharmacologic treatment of bipolar disorder, an earlier observation of menstrual abnormalities preceding the onset of bipolar symptoms and this report’s finding of long menstrual cycles in the presence of oral contraceptive use suggest that there may be an underlying vulnerability to long or abnormal menstrual cycles in women with bipolar disorder. Reference 1. Rasgon NL, et al. Bipolar Disord . (in press).
  • Increased Insulin Resistance in Women With Bipolar Disorder. Forty-two women with bipolar disorder were evaluated for insulin resistance by Rasgon et al. 1 Of the 42 women, 12 (28%) were receiving lithium, 24 (57%) were receiving valproate, 15 (38%) were receiving other anticonvulsants, and 11 (26%) were receiving antipsychotics. Each subject was receiving more than 1 of these medications. The investigators found that 19 (45%) of women in the study had a homeostasis model assessment (HOMA) ratio >2.3, which was a sign of insulin resistance. No differences were found between anticonvulsant or antipsychotic intake and the development of insulin resistance. The conclusion was that insulin resistance is common among bipolar women treated with anticonvulsants. The question whether the rate of insulin resistance is inherently high or whether this condition is a result of its treatment remains to be determined. Reference 1. Rasgon NL, et al. Poster presented at the American Psychiatric Association annual meeting, Philadelphia, Pa, May 18-23, 2002.
  • PCOS. Characteristics and Causes. PCOS is a complex endocrine disorder affecting women in their reproductive years that is characterized by increased androgen production and ovulatory dysfunction. It is the leading cause of anovulatory infertility. PCOS is different from polycystic ovaries (PCO), a condition characterized by at least 10 subcapsular follicular cysts, measuring 2 to 8 mm in diameter, arranged around or within thickened ovarian stroma. PCO is not intrinsically pathologic, and as many as 25% of women with a radiographic finding of PCO have no endocrine or menstrual irregularities. It is believed that PCOS is caused by interactions between genetic, endocrine, metabolic, neurologic, and environmental factors.
  • Isojärvi et al 1993: Correlation Between AEDs and Menstrual Disturbances. The issue of the role of specific AEDs, in particular valproate, in the pathogenesis of menstrual disturbances was raised by a series of retrospective studies by Isojärvi and colleagues. In his first study, the investigators compared 238 women with epilepsy with 51 healthy untreated controls. Twenty-nine (12%) of the women with epilepsy were treated with valproate alone, 120 (50%) with carbamazepine alone, 12 (5%) with a combination of both valproate and carbamazepine, 62 (26%) with other AEDs, and 15 (6%) remained untreated. 1 Menstrual disturbances were reported by 45% of women receiving valproate, 19% receiving carbamazepine, 25% receiving a combination of both, 13% of those receiving other medications, and 0% of the untreated women. The finding that no untreated women with epilepsy had abnormal menstruation raises the question of ascertainment bias in light of the rates observed in other studies. 1,2 When vaginal ultrasonography was performed on the 98 women with epilepsy and a history of menstrual problems, the investigators found polycystic ovaries in 43% of valproate-treated patients, 22% of carbamazepine-treated patients, and 50% of the combination group. References 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 2. Isojärvi JIT, et al. N Engl J Med . 1993;329:1383-1388.
  • Isojärvi et al 1996: PCO, Hyperandrogenism, or Both From Valproate or Carbamazepine. In a second study by Isojärvi et al, investigators compared 22 women receiving valproate monotherapy with 43 women receiving carbamazepine monotherapy. 1 In the valproate group, 64% of women had PCO (determined by vaginal ultrasonography), hyperandrogenism, or both. In women taking carbamazepine, 21% had one or both conditions, and in a control group of healthy women, 19% had one or both conditions. Fasting insulin levels were slightly higher in the valproate-treated group (16.9±10.5) than the carbamazepine group (15.4±10.5) and the control group (9.6±5.1). The investigators also reported that 50% of women treated with valproate had marked weight gain (mean, 21.0 kg). 2 The weight gain was progressive and was associated with hyperinsulinemia and low serum levels of insulin-like growth factor protein I, which the investigators claimed may lead to hyperandrogenism and PCO. 1 References 1. Isojärvi JIT, et al. Ann Neurol . 1996;39:579-584. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65.
  • Isojärvi et al 1993 and 1996: Analysis. These two studies by Isojärvi et al had many of the same design problems. 1,2 In both studies, the authors do not distinguish between PCO and PCOS. Using the NIH criteria for the diagnosis of PCOS, none of the women on valproate with PCO had PCOS. 3 Some authors also have expressed concern about these studies because of their lack of pretreatment data regarding ovarian structure and function and their cross-sectional, retrospective design. 3 References 1. Isojärvi JIT, et al. Ann Neurol . 1996;39:579-584. 2. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 3. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55.
  • Isojärvi et al 1998: Testosterone and Insulin Levels After Switch From Valproate to Lamotrigine. Isojärvi et al next studied the effects of switching 16 women with epilepsy treated with valproate, who had PCO or hyperandrogenism, to lamotrigine. 1,2 During the year following the switch to lamotrigine, patients lost weight (with significant decreases in body mass index), had lower androgen levels, and showed a decrease in the number of ovarian follicles visualized. The investigators also found that fasting insulin levels decreased and lipid profiles improved. The weight loss was marked and was associated with biochemical improvement and the restoration of regular menstrual cycles in the women. It has been reported that weight loss may restore menstrual regularity and reduce insulin and lipid levels. Some authors have suggested that women who are predisposed to develop PCOS because of genetic or other factors may develop PCOS when exposed to an agent that causes weight gain. Isojärvi et al concluded that their findings raise serious concerns about the risks associated with the use of valproate in patients with epilepsy. They claimed that the advantages of long-term valproate use should be weighed against the risks, and an alternative treatment considered in patients with obvious weight gain during valproate treatment, especially in young women with primary generalized epilepsy. 2 References 1. Duncan S. Epilepsia . 2001;42(suppl 3):60-65. 2. Isojärvi et al. Ann Neurol . 1998;43:446-451.
  • Isojärvi et al 1998: Analysis. This study started with 16 women but results were available for only 12. Four patients withdrew from the study: 1 due to pregnancy, 1 from rash, and 2 because of relapse of their juvenile myoclonic epilepsy. 1 Another concern about the study is that criteria for patient selection was not provided, so possible selection bias cannot be sufficiently evaluated. During valproate treatment, 11 (91%) of 12 women had at least 1 polycystic ovary; after switching to lamotrigine, 7 (83%) of women had a polycystic ovary, which is not a statistically significant change. 1 The relapse experienced by 2 women after stopping valproate therapy is a significant clinical issue. It should be noted that patients switched from valproate to lamotrigine therapy often are not able to adequately control their seizures. In one study, 202 (59%) of 340 patients switched from valproate to lamotrigine failed monotherapy, especially patients with juvenile myoclonic epilepsy. 2 Criteria for patient selection was not provided; possible selection bias cannot be evaluated. Another concern with the study is that only obese women on valproate were chosen for the study; it was not randomized for weight. References 1. Isojärvi JI, et al. Ann Neurol . 1998;43:446-451. 2. Dean JC, et al. Poster presented at American Epilepsy Society Annual Meeting, 2001.
  • Testosterone Concentrations in Women With Epilepsy Treated With Valproate or Lamotrigine. In an open-label, multicenter, cross-sectional, observational study, Taylor et al compared the effects of lamotrigine or valproate monotherapy on the endocrine and lipid profiles and menstrual irregularities of women with epilepsy. 1 The study included 222 women treated for epilepsy for at least 8 months. At follow-up, the investigators measured weight, androgen levels, HDL, LDL, triglycerides, and insulin levels. Results: Mean weight in the valproate group increased from 63.0 kg to 67.7 kg, while mean weight in patients taking lamotrigine stayed the same (71.5 kg), though mean weight was higher in the valproate group. Testosterone and other androgen levels increased more in patients taking valproate, but both groups were within the normal range (21 ng/dL for lamotrigine-treated women versus 28 ng/dL for valproate-treated women; most experts consider abnormal testosterone levels to be greater than 70 ng/dL). Total cholesterol and LDL levels were lower in the valproate group. Insulin levels were not statistically significantly different between the 2 groups. About twice as many patients taking lamotrigine reported at least 1 cycle length less than 25 days (12% of valproate patients versus 25% of lamotrigine patients). Reference 1. Taylor A, et al. Poster presented at: American Psychiatric Association annual meeting; May 5-10, 2001; New Orleans, Louisiana.
  • Taylor et al 2001: Analysis. Taylor et al compared the effects of lamotrigine or valproate monotherapy on endocrine and lipid profiles and menstrual irregularities of women with epilepsy. The researchers found: 1 Testosterone and other androgen levels increased more in patients taking valproate, but both groups were within normal range Total cholesterol and LDL levels were lower in the valproate group Insulin levels were similar in both treatment groups Another finding was that twice as many patients taking lamotrigine reported at least 1 cycle length less than 25 days (21% of valproate patients versus 25% of lamotrigine patients. Reference 1. Taylor A, et al. Poster presented at: American Psychiatric Association annual meeting; May 5-10, 2001; New Orleans, Louisiana.
  • No Association Found Between PCOS and Valproate or Carbamazepine Therapy. Bauer et al conducted a study of 93 women with epilepsy and had results that did not support those of Isojärvi. 1 In this study, PCOS was defined using NIH criteria. The researchers compared PCOS among 4 groups of women with epilepsy: an untreated group, a valproate-treated group, a carbamazepine-treated group, and those receiving polytherapy. The incidence of PCOS was as follows: untreated group: 10.5% (2/19); carbamazepine group: 10% (2/20); valproate group: 11.1% (2/18); and polytherapy: 0%. This study used an internationally accepted definition of PCOS and made the distinction between PCO and PCOS. 1 The investigators concluded that the results from this study suggest that manifestations of PCOS in patients with focal epilepsy are not related to the administration of either valproate or carbamazepine. 2 Some authors have suggested that if clinicians are concerned about the literature on PCOS and valproate, they can use valproate with caution in young women with a family history suggestive of PCOS. If women with epilepsy have marked weight gain or menstrual irregularity, they should be referred to an endocrinologist for assessment. Valproate remains a first-line option for the treatment of epilepsy in young women. 1 References 1. Duncan S. Epilepsia . 2001; 42(suppl 3):60-65. 2. Bauer J, et al. Epilepsy Res . 2000;41:163-167.
  • Bauer et al 2000: Analysis. Bauer et al studied 4 groups of women with epilepsy: an untreated group, a valproate-treated group, a carbamazepine-treated group, and those receiving polypharmacy. 1 Using NIH criteria for PCOS, investigators found no relationship between the administration of valproate or carbamazepine and the development of PCOS. The investigators concluded that the results from the study suggest that the manifestations of PCOS in women with focal epilepsy are not related to the administration of valproate or carbamazepine. Reference 1. Bauer J, et al. Epilepsy Res . 2000;41:163-167.
  • Reproductive Endocrine Disorders in Epilepsy Not Associated With AEDs. Bilo et al attempted to determine whether the increased frequency of reproductive endocrine disorders in women with epilepsy is linked to the seizure disorder or the use of AEDs. 1 The investigators subjected 50 epileptic women of reproductive age to clinical endocrinological evaluation, hormonal assessment, and ovarian ultrasonography. Reproductive endocrine disorders were diagnosed in 16 (32%) women. These consisted of: PCOS in 13 women Hypothalamic amenorrhea in 2 women Luteal phase deficiency in 1 woman There was no significant association of these disturbances with epilepsy type or AED treatment. Bilo et al concluded that the results from their study indicated that the prevalence of disordered ovulation, especially PCOS, is increased in epilepsy and that this phenomenon is independent of AED or type of seizure disorder. Reference 1. Bilo L, et al. J Clin Endocrinol Metab . 2001;86:2950-2956.
  • Bilo et al 2001: Analysis. In a study of 50 women of reproductive age with various forms of epilepsy, the investigators found no significant association between reproductive endocrine disorder (such as PCOS, hypothalamic amenorrhea, and luteal phase deficiency) and epilepsy type or antiepileptic drug treatment (therapy with or without valproate). The investigators concluded from the results from their study that the prevalence of anovulation, especially PCOS, is increased in epilepsy and that this phenomenon is independent of AED use or type of seizure disorder. Reference 1. Bilo L, et al. J Clin Endocrinol Metab . 2001;86:2950-2956.
  • Valproate Not Associated With Increased Menstrual Disorders, PCO, or Both. Luef et al investigated 43 women with epilepsy to determine whether valproate, lamotrigine, or carbamazine use is associated with an increased incidence of PCOS. They found that 11 (25.6%) had PCO as determined by ultrasound and 3 (7%) had PCOS. The investigators noted that, in contrast with the studies of Isojärvi et al, they found no increased frequency of menstrual disorders in women receiving valproate compared with women treated with either carbamazepine or lamotrigine. 1 They did find increased androgen levels in women with valproate therapy, though there was no increase in the occurrence of PCO. Reference 1. Luef G, et al. Epilepsy Res . 2002;48:91-102.
  • Luef et al 2002: Analysis. The investigators reported that, in contrast with the studies of Isojärvi et al, they found no increased frequency of menstrual disorders in 43 women receiving valproate (n=22) compared with women receiving carbamazepine or lamotrigine (n=21) after at least 2 years of treatment. They did report an increase in androgen levels in women treated with valproate. 1 A limitation of this study was its use of a small sample size and the cross-sectional study design. Reference 1. Luef G, et al. Epilepsy Res . 2002;48:91-102.
  • Larger Study Reaffirms No Association Between Valproate and PCO. Luef et al investigated 105 women with epilepsy to determine the role of valproate and carabamazepine in the development of PCO. Upon ultrasound scan, 27% of the patients were found to have PCO. Twenty-eight percent of the women reported menstrual disturbances. 1 Patients treated with valproate had slightly lower incidence of both menstrual disturbances (11%) and PCO (12%) than did those treated with carbamazepine (16% and 14%, respectively). Reference 1. Luef G, et al. J Neurol . 2002;249:835-841.
  • 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 treated with valproate compared with women treated with carbamazepine. They did find significant increases in postprandial insulin, C-peptide, and proinsulin levels in the valproate group versus the carbamazepine group. The incidence of PCO in the general population has been reported to be between 20% and 30%. 1 In this study, the PCO incidence rate in women with epilepsy (27%) falls within the range of the general population rate, indicating no increase in the incidence of PCO with valproate treatment. Reference 1. Luef G, et al. J Neurol . 2002;835-841.
  • Women With Bipolar Disorder: No PCOS-Like Changes With Lithium or Divalproex Treatment. Rasgon et al studied 22 outpatients with DSM-IV diagnosis of bipolar disorder between the ages of 18 and 45 years to determine whether PCOS is associated with divalproex treatment in this patient population. 1 None of the patients met the criteria for PCOS at the beginning of the study. 1 Ten patients received divalproex sodium, 10 received lithium, and 2 received divalproex plus lithium (combination therapy). The investigators reported after a mean treatment length of >12 months that none of the women in the study developed clinical or endocrinological symptoms associated with PCOS. Ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Rasgon et al noted that they did not observe the PCOS symptoms reported by Isojärvi et al in their research in epileptic patients, 2 even though the mean dose of divalproex was higher, although the treatment length with divalproex was longer (approximately 7 years) in the Isojärvi et al study than in the Rasgon et al study (approximately 3 years). References 1. Rasgon NL, et al. J Clin Psychiatry . 2000;61:173-178. 2. Isojärvi JI, et al. N Engl J Med . 1993;329;1383-1388.
  • Rasgon et al 2000: Analysis In their study of 22 women with bipolar disorder, Rasgon et al reported that none of the women treated with lithium, divalproex, or both developed symptoms of PCOS after >12 months of treatment. The treatment length was 68.8±51.0 months for patients in the lithium group, 34.1±30.4 for patients in the divalproex group, and 12±0 for patients in the lithium plus divalproex group. 1 Ultrasound revealed an increased number of ovarian follicles in 1 patient taking lithium and in none of the patients taking divalproex. Rasgon et al noted that they did not observe the PCOS symptoms reported by Isojärvi et al in their research with epileptic patients. 2 The difference between the 2 studies was that the mean treatment length was longer in the Isojärvi et al study, but the dose of divalproex was higher in the Rasgon et al study. The researchers reported that the bipolar women in the study reported high rates of menstrual disturbances, suggesting that the hypothalamic-pituitary-gonadal axis may be compromised in some women with bipolar disorder. 1 References 1. Rasgon NL, et al. J Clin Psychiatry . 2000;61:173-178. 2. Isojärvi JI, et al. N Engl J Med . 1993;329;1383-1388.
  • Association of Epilepsy Type, AED, and Ovulatory Function. Morrell et al evaluated whether women with epilepsy are more likely to have anovulatory cycles and assessed the association of epilepsy syndrome and AED to ovulatory dysfunction. 1 Subjects in the study were aged 18 to 40 years. They consisted of women without epilepsy (n=23) and women wither either localization-related epilepsy (LRE, n=59) or idiopathic (primary) generalized epilepsy (IGE, n=35). The women received carbamazepine, phenytoin, phenobarbital, valproate, lamotrigine, or gabapentin as monotherapy for 6 months or more. The investigators found that women with IGE had more anovulatory cycles than did controls and women with LRE, although the differences were not statistically significant. When ovulatory function was assessed by AED, there was no statistically significant association between current AED and anovulatory cycles. However, when the investigators considered AEDs used in the past, use of valproate currently or within the preceding 3 years was associated with a higher frequency of anovulatory cycles. There was no statistically significant difference in the percentage of women who had polycystic appearing ovaries (PCAO). Reference 1. Morrell MJ, et al. Ann Neurol . (In press).
  • Morrell et al 2002: Analysis. A limitation of the study by Morrell et al was that the effects of the epilepsy syndrome could not be separated from the effects of AEDs. Because AED selection was guided to some extent by the epilepsy syndrome, each syndrome did not equally represent all AED groups. Five of the 6 study drugs were used in women with LRE, while only 3 of the study drugs (phenytoin, lamotrigine, and valproate) were used in women with IGE. In addition, the investigators did not control for past AED exposure; effects from an individual AED are difficult to determine in a condition such as epilepsy in which patients are likely to receive multiple medications over the course of the disease. 1 A study of newly diagnosed women with epilepsy receiving AEDs de novo would be better able to define drug specific effects. Reference 1. Morrell MJ, et al. Ann Neurol . (In press).
  • Menstrual Abnormalities in Women With Bipolar Disorder. Thirty-two women with bipolar disorder were included in a study by O’Donovan et al and divided into 2 groups: those receiving valproate (n=17) and those who were not currently receiving valproate (n=15). 1 These 2 groups were compared with a normal (no psychiatric disorder) group of 22 women. The investigators reported that significantly more women receiving valproate reported menstrual abnormalities (47%) than women not receiving valproate (13%) and controls (0%). Seven of 17 (41%) of women with bipolar disorder where found to have PCOS. While 43% of the women treated with valproate were obese (BMI >25), there was also a high rate of obesity in the other groups: 57% of the nonvalproate group were obese and 46% of controls were obese. The investigators noted that, unlike Isojärvi’s 1996 study, 2 they were not able to find a statistical difference between women treated with valproate and those not treated with valproate in terms of the number of women who were obese as measured by BMI scores or by examining the number of women who had BMI scores over 25, 27, or 30. They stated that “this finding argues against a casual link between valproate, obesity and the presence of PCOS features.” 1 Reference 1. O’Donovan C, et al. J Clin Psychiatry . 2002;63:322-330. 2. Isojärvi JI, et al. Ann Neurol . 1996;39:579-584.
  • O’Donovan et al 2002: Analysis. Although O’Donovan et al said their study suggested that bipolar adult women treated with valproate may be at high risk for developing PCOS or PCOS-life features, they stated that “the interpretation of data must be done with caution,” because the retrospective design of the study and use of self-report may be inaccurate, as it may be difficult for women to remember exact times and periods in which they had menstrual abnormalities. 1 The investigators also noted that the large number of women who did not respond to the questionnaire used in the study “is a significant limitation to the study,” since it is possible that the women who did not respond had no menstrual problems. They noted that a larger sample and control group are needed to be able to differentiate problems for women with bipolar disorder compared with women receiving valproate. They added that current “stringent guidelines” for valproate-treated women, which suggest baseline and yearly lipid profile as well as BMI calculation with each visit may be “premature and excessive.” Reference 1. 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. Ferin et al investigated the relationship between long-term therapy with valproate and menstrual and reproductive disturbances in 7 healthy rhesus monkeys with normal menstrual cycles. 1 These monkeys were compared with a control group of 7 medication-free, normally cycling monkeys. The treatment duration was 12.7 to 15.7 months. The investigators reported that there were no statistically significant differences between the 2 groups in testosterone or LH levels during the first, second, or last trimester of valproate treatment. In addition, no statistically significant differences were observed between the control and valproate-treated groups in terms of the glucose or insulin response to a glucose tolerance test. Ferin et al examined all 14 ovaries from the 7 valproate-treated monkeys and reported that no histological characteristics of PCOS were observed in any of the ovaries. All 14 ovaries were found to have histological evidence of ovulation. The study demonstrated that long-term treatment with valproate in normal monkeys does not induce cyclic irregularities, anovulation, or amenorrhea. Ferin et al concluded that their results do not support the hypothesis that valproate per se is responsible for the induction of PCOS. Reference 1. 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: Response to Glucose Tolerance Test. Ferin et al investigated the relationship between long-term therapy with valproate and menstrual and reproductive disturbances in 7 healthy rhesus monkeys with normal menstrual cycles. 1 These monkeys were compared with a control group of 7 medication-free, normally cycling monkeys. The treatment duration was 12.7 to 15.7 months. The investigators reported that there were no statistically significant differences in testosterone or LH levels during the first, second, or last trimester of valproate treatment. In addition, no statistically significant differences were observed between the control and valproate-treated groups in terms of the glucose or insulin response to a glucose tolerance test. The study demonstrated that long-term treatment with valproate in normal monkeys does not induce cyclic irregularities, anovulation, or amenorrhea. Ferin et al concluded that their results do not support the hypothesis that valproate per se is responsible for the induction of PCOS. Reference 1. Ferin M, et al. Poster presented at the American Epilepsy Society annual meeting; Seattle, Washington; December 6-11, 2002.
  • Ferin et al 2002: Analysis. In a study by Ferin et al, long-term treatment (12 to 15 months) with valproate in 7 healthy rhesus monkeys was found not to be associated with differences in testosterone or LH levels compared with a control (no treatment) group of 7 monkeys. 1 In addition, both groups were also similar in terms of their glucose and insulin responses to a glucose tolerance test. All 14 ovaries of the 7 valproate-treated monkeys were reviewed on gross and microscopic examinations. The characteristic histological features of PCOS were not observed in any of the ovaries. All 14 ovaries showed histological evidence of ovulation. The investigators concluded that their results do not support the hypothesis that treatment with valproate per se is responsible for the induction of PCOS. 1 Reference 1. Ferin M, et al. Poster presented at the American Epilepsy Society annual meeting; Seattle, Washington; December 6-11, 2002.
  • Summary of Literature on PCOS and Valproate. In an extensive review of the literature, Genton et al 1 addressed the issue raised by Isojärvi et al concerning the possibility of an increased incidence of PCOS in women with epilepsy treated with valproate. They noted that: PCO are a common finding, with a prevalence of >20% in the general population, while PCOS is comparatively rare. Few women with PCO have fully developed PCOS. Evidence suggests that PCOS is the consequence of multiple abnormalities, including genetic and environmental factors. Metabolic changes implicated in the pathogenesis of PCOS include hyperinsulinism, which may be affected by environmental factors. PCOS appears to be more frequent in women with epilepsy, but there are no reliable data showing a greater prevalence in women treated with valproate. Recent studies by Isojärvi et al may have been biased by the retrospective selection of patients. It is also interesting to note that a further analysis of some of these studies shows that none of the women meet the NIH criteria for PCOS. 2 To date, there are no data that contraindicate the use of valproate in women with epilepsy or bipolar disorder. Switching an adequately controlled patient with epilepsy or bipolar disorder from valproate should be done with caution. 3 References 1. Genton P, et al. Epilepsia . 2001;42:295-304. 2. Ernst CL, et al. J Clin Psychiatry . 2002;63(suppl 4):42-55. 3. Dean JC, et al. Poster presented at American Epilepsy Society Annual Meeting, 2001.
  • PCOS in Women With Epilepsy. Management Goals. Management of PCOS consists of 2 goals: treatment of conditions, such as hyperandrogenism and anovulation, that are undesirable but not life-threatening, and the management of conditions with serious health consequences, such as metabolic and cardiovascular diseases or risk factors. 1,2 Women with PCOS typically seem healthy, but many have insulin resistance and hyperinsulinemia, abnormal lipid and lipoprotein levels, and altered fibrinolysis. 1 Physicians managing women with PCOS should diagnose and treat evidence of lipoprotein abnormalities. 1 Treatments include: Hyperandrogenism : hirsutism can be treated with hair removal; antiandrogen therapy can be used for both hirsutism and alopecia. 2 Anovulation : clomiphene citrate, gonadotropins, gonadotropin-release hormone. Insulin resistance : insulin sensitizing agents, such as metformin. 3 Elevated triglycerides and LDL, decreased HDL : agents that lower triglycerides and LDL and raise HDL, such as statins and fibrates. 4 Obesity : calorie restriction The choice of AED may also influence levels of lipoproteins. Valproate has been associated with decreased levels of total cholesterol and LDL cholesterol. 5 References 1. Lobo RA, et al. Ann Int Med . 2000;132:989-993. 2. Franks S. N Engl J Med . 1995;333:853-861. 3. Hopkinson ZE, et al. BMJ . 1998;317:329-332. 4. JAMA . 2001;285:2486-2497. 5. Calandre EP, et al. Acta Neurol Scand . 1991;83:250-253.
  • Failure to Adequately Control Seizures After Switch From Valproate to Lamotrigine. In a retrospective chart review, Dean et al analyzed data from 2468 outpatients treated for epilepsy from August 1996 to August 2000. They examined patients with generalized epilepsy, including generalized tonic-clonic seizures, absence seizures, juvenile myoclonic epilepsy, myoclonic seizures, and atonic seizures, who were controlled with valproate monotherapy but switched to lamotrigine because of adverse events. 1 A total of 340 patients (129 male, 211 female) were switched from valproate to lamotrigine. The investigators reported that 202 (59%) patients failed successful conversion to lamotrigine monotherapy. The patients who failed were as follows, by seizure type: Juvenile myoclonic epilepsy: 120/136 (88%) Generalized tonic-clonic seizures: 72/170 (42%) Absence seizures: 6/17 (35%) Myoclonic jerks: 4/7 (57%) The investigators concluded that a substantial number of patients with generalized epilepsy, particularly those with juvenile myoclonic epilepsy, may not be adequately controlled with the conversion to lamotrigine therapy. They noted that switching therapy should be considered with caution in patients who are controlled on present medication regimens. Reference 1. Dean JC, et al. Poster presented at American Epilepsy Society Annual Meeting, 2001.
  • Effects of Antiepileptic Drugs on Oral Contraception Efficacy. The efficacy of oral contraception (OC) can be impaired by concomitant use of AEDs that induce liver enzymes (eg, barbiturates, carbamazepine, oxcarbazepine, phenytoin, topiramate, and tiagabine), which may be secondary to enhanced hepatic metabolism of the OC hormones. 1,2 AEDs that do not significantly induce liver enzymes—such as valproate, felbamate, gabapentin, and lamotrigine—do not reduce levels of the OC hormones and therefore should not increase the risk of OC failure. 1 References 1. Morrell MJ. Neurology . 1998;51(suppl 4):S21-S27. 2. Hachad H, et al. Ther Drug Monit . 2002;24:91-103.
  • PCOS: Conclusions. PCOS is a serious reproductive endocrine disorder with an increased incidence in women with epilepsy. PCOS-like symptoms also may be more frequent in women with bipolar disorder than in the general population, though more data are needed to confirm this. PCOS is characterized by ovulatory dysfunction and hyperandrogenism. It is important to distinguished PCOS from PCO, a condition that is not intrinsically pathologic and that is much more prevalent in the female population. There are no reliable data showing a greater prevalence of PCOS in women treated with any AED. Studies that have reviewed a possible connection between PCOS and AEDs, especially valproate, have suffered from design flaws that limit their value, such as failing to distinguish between PCO and PCOS or not using NIH criteria for PCOS. Choice of AED for women of reproductive age with epilepsy or bipolar disorder should be based on the most effective agent for controlling symptoms.
  • Transcript

    • 1. 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.
    • 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 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.
    • 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 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 .
    • 9. 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
    • 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 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
    • 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 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.
    • 17. 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
    • 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)
      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
    • 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 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
    • 25. 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
    • 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. 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
    • 31. Review of Clinical Data
    • 32. 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
    • 33. 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
    • 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 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. † ‡ † § § §
    • 36. 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
    • 37. 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
    • 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. 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%)
    • 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 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
    • 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. 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
    • 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 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, %
    • 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 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
    • 48. 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
    • 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).
    • 51. 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, %
    • 52. 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.
    • 53. 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.
    • 54. 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
    • 55. 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”
    • 56. 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
    • 57. Proper Management of Patients With PCOS and Epilepsy
    • 58. 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.
    • 59. 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
    • 60. 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
    • 61. PCOS Conclusions
        • 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

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