TREATMENT OF BIPOLAR DISORDER IN CHILDREN AND ADOLESCENTS - PART 9 doc

However, as suggested by Chappell, Markowitz, and Jackson 1999,the diagnosis of PCOS is generally made through a combination of clinical,biochemical, and ultrasonographic findings.DIFFER

PA RT I I I

OTHER ISSUES

C H A P T E R 1 7

Polycystic Ovary Syndrome

se-rious endocrine disorder that affects women in their reproductive years.The disorder was first recognized in 1935 by two gynecologists, Stein andLeventhal (1935) They described a group of women who had a constella-tion of infertility and several menstrual irregularities and were obese Theywere also found to have enlarged ovaries with multiple cysts at laparotomy(Zawadski & Dunaif, 1992) Although it has come to be known as PCOS,the ovarian morphology is a nonspecific finding Approximately 20% ofnormal women can have classic polycystic ovarian morphology on ultra-sound examination (Dunaif, 1997) Subsequently, others have reportedPCOS to be a disorder characterized by ovulatory dysfunction and hyper-androgenism that is thought to have a higher prevalence in women with ep-ilepsy and, perhaps, bipolar disorder

Unlike the earlier reports by Stein and Leventhal (1935), others havenoted that women with PCOS can be lean, and the symptoms of androgenexcess may be absent PCOS is the leading cause of hormonally related in-fertility and hirsutism and has been associated with multiple reproductiveand metabolic disorders Approximately 80% of women with oligomen-orrhea, the clinical consequence of chronic anovulation, have PCOS (Dunaif,1997) PCOS is also a major risk factor for type 2 diabetes mellitus (DM) inwomen (Legro et al., 1999)

333

An association between the development of PCOS and the use ofantiepileptic drugs was first suggested by Isojärvi et al (1993) This sugges-tion was based on clinical observations that women with epilepsy who re-ceived an antiepileptic drug experienced an increased rate of menstrual ab-normalities Although there are no reports of PCOS in teenage girls, use ofmood stabilizers such as valproate is increasing for the treatment of bipolar

disorders in children and adolescents Three letters to the editor of the

Jour-nal of the American Academy of Child and Adolescent Psychiatry (Garland

& Behr, 1996; Eberle, 1998; Johnston, 1999) draw attention to this tial association between use of valproate and development of PCOS in teenagegirls They stimulate awareness for both clinicians and researchers and askfor prospective studies to be conducted to shed light on this possible associ-ation between the use of mood stabilizers (specifically valproate), otherantiepileptic medications, and PCOS

poten-PCOS is associated with several reproductive, metabolic, and generalhealth disorders, including increased risk of miscarriage, insulin resistance,hyperlipidemia, and cardiovascular disease Endometrial, ovarian, andbreast cancer have all been reported to be more common in women withPCOS (Hardiman, Pillay, & Atiomo, 2003; Balen, 2001; Coulam, Annegers,

& Kranz, 1983; Schildkraut et al., 1996) Elevated levels of circulating trogen and the lack of cycling shedding of the endometrium are considered

es-to be the likely etiology of the increased risk for endometrial carcinoma inwomen with PCOS (Rasgon, 2004; Hardiman et al., 2003; Siiteri, 1987) In

a large case control study examining the relationship between endogenoussteroid hormones and endometrial cancer, Potischman and colleagues(1996) found increased risk of endometrial cancer in women with de-creased sex-hormone-binding globulin (SHBG) and increased androgen lev-els

Although obesity is not always present in women with PCOS, it is acommon finding, with reports of up to 50% of women with PCOS beingobese, described primarily as the android-type obesity, with an increase inthe waist–hip ratio (Lobo & Carmina, 2000) It has been postulated thatobesity within itself may promote the development of PCOS through pe-ripheral aromatization of androgen to estrogen within adipose tissue(Franks, 1995; Siiteri, 1987) Subsequently this obesity contributes to thehigh rates of type 2 diabetes and hyperlipidemia and increases the risk ofcardiovascular disease in women with PCOS (Rasgon, 2004)

DEFINITION

PCOS is characterized by both hormonal and metabolic abnormalities parate definitions of this syndrome have been proposed A contemporaryworking definition is hyperandrogenism and chronic anovulation (i.e.,

Dis-menstrual abnormalities and reproductive morbidity) in the absence ofidentifiable pituitary or adrenal pathology Interestingly, polycystic ovariesare not necessary for the diagnosis to be made (Dunaif & Thomas, 2001;Lobo & Carmina, 2000).

Many of these women have endocrine abnormalities such as elevatedtestosterone and/or luteinizing hormone (LH ) levels (Franks, 1995) How-ever, some women with polycystic ovaries can be entirely endocrinologi-cally normal Moreover, approximately 10% of women with all the features

of the endocrine syndrome have normal-appearing ovaries by ultrasoundexamination (Ehrmann et al., 1995) Accordingly, the recommended diag-nostic criteria for PCOS at the 1990 National Institutes of Health (NIH)conference on polycystic ovary syndrome (Zawadski & Dunaif, 1992) werehyperandrogenism and chronic anovulation in the absence of specific dis-eases of the ovaries, adrenals, or pituitary It is important to differentiatethis endocrine syndrome from the ovarian morphological change of poly-cystic ovaries Outside the United States, it is still typical to diagnosewomen by the appearance of their ovaries on ultrasound examination.These differing diagnostic criteria for PCOS account for many of the dis-crepant findings in the literature It appears, however, that polycystic ova-ries function abnormally, even in the absence of the peripheral endocrinesyndrome, both in the steroidogenic activity of the theca interna and in thefollicular responses to exogenous follicle-stimulating hormone (FSH; Franks,1995)

Therefore, the definition of PCOS differs in the United States and inEurope in the following ways:

anatomical changes need not be present to establish diagnosis

in the presence of one or more clinical signs of endocrine tion, such as menstrual irregularities, hirsutism, or infertility.The diagnostic criteria for PCOS on which participants agreed at the 1990NIH–PCOS consensus conference (Zawadski & Dunaif, 1992; Duncan,2001; Ernst & Goldberg, 2002), are as follows:

oligomenor-rhea, or amenorrhea)

function, such as hyperprolactinemia, hypothyroidism, adrenal perplasia, or Cushing’s syndrome

multifollicu-lar ovaries, or hyperandrogenism in isolation

However, as suggested by Chappell, Markowitz, and Jackson (1999),the diagnosis of PCOS is generally made through a combination of clinical,biochemical, and ultrasonographic findings.

DIFFERENCES BETWEEN PCOS AND POLYCYSTIC OVARIES

Whereas PCOS is a complex endocrine disorder characterized by metabolicand endocrine abnormalities that affects women in their reproductiveyears, polycystic ovaries are a common but not intrinsically pathologicaloccurrence in 22–30% of the general female population (Luef, Abraham,Haslinger, et al., 2002; Genton et al., 2001) The accepted definition ofpolycystic ovaries by ultrasonographic and anatomical criteria is the pres-ence of at least 10 subcapsular follicular cysts, measuring 2–8 mm in diam-eter, arranged around or within thickened ovarian stroma (Adams et al.,1985; Adams, Polson, & Franks, 1986; Duncan, 2001) As many as 25%

of women with radiological findings of polycystic ovaries have no crine or menstrual irregularities, suggesting that an isolated finding ofpolycystic ovaries may be a normal variation and may not necessarily implyaltered fertility (Genton et al., 2001) It is therefore important to distin-guish between these two conditions when interpreting clinical studies(Ernst & Goldberg, 2002) A case control study of 258 women with andwithout other hormonal or metabolic symptoms of PCOS, showed thatthere was no significant effect on fertility (Hassan & Killick, 2003) There-fore, the finding of polycystic ovaries in otherwise healthy women may notnecessarily predict reproductive dysfunction (Rasgon, 2004)

endo-Other disorders that need to be considered in the differential for PCOS clude: nonclassic adrenal 21-hydroxylase deficiency (prevalence 1–5%), hyper-prolactinemia and Cushing’s syndrome (occasional occurrence), surreptitiousandrogen use (rare), extreme insulin resistance syndromes, for example, type A(rare), and ovarian and adrenal androgen-secreting neoplasms (very rare)

in-PREVALENCE

Only recently have there been studies of the prevalence of the classic crine syndrome of hyperandrogenism and chronic anovulation The preva-lence of PCOS in the general population of reproductive-age women has beenestimated to be between 4 and 12%, without any differences in prevalence be-tween Caucasian and African American women (Dunaif & Thomas, 2001;Lobo & Carmina, 2000; Knochenhauer et al., 1998) However, most reportsshow a higher prevalence (10.5–26%) of PCOS in women with epilepsy than

endo-in the general population (Bauer et al., 2000; Bilo et al., 2001) Franks (1995)reported that 37% of women with amenorrhea and 90% with oliomenorrhea

had PCOS Bauer et al (2000) studied 93 women with epilepsy and foundthat the incidence of PCOS was 10.5% in an untreated group, 11.1% in avalproate-treated group, and 10% in a carbamazepine-treated group Thereare no prevalence studies in females under the age of 18 years.

Valproate is an approved treatment for epilepsy syndrome Bipolartreatment guidelines from Canada and the United States recommendvalproate as a first-line strategy in the acute treatment of bipolar disorder(O’Donovan et al., 2002) Most persons with bipolar disorder requiremaintenance treatment, which necessitates the need for careful appraisal

of long-term tolerability and safety issues There have been reports ofvalproic acid inducing PCOS in females with epilepsy (Franks, 1995).These observations have initiated preliminary investigation in bipolar dis-order (Dunaif & Thomas, 2001; Knochenhauer et al., 1998; Yen, 1991).Recently, O’Donovan et al (2002) reported that valproate-treated fe-males with bipolar disorder exhibited a high prevalence of menstrual ir-regularities and exhibited ultrasonographically confirmed polycystic ova-ries (41%) A study of ambulatory females with DSM-IV-defined bipolardisorder between the ages of 18 and 45 (10 receiving valproate mono-therapy) failed to identify any biochemical or ultrasonographic evidence

of PCOS in females receiving valproate or lithium (Rasgon et al., 2000)

It was noted by both groups that bipolar females exhibited a higher alence of menstrual disturbances than the general population Othershave described the potential associations between PCOS and valproate(Herzog, 1996; Post et al., 2001)

prev-Although it awaits to be established whether females with bipolar order manifest a higher prevalence of primary reproductive endocrine dis-orders, they appear to be more overweight or obese than the general popu-lation (Suppes, Leverich, & Keck, 2001) Valproate and several otherpsychotropic agents impart substantial weight gain (Ferriman & Gallwey,1961; Roste et al., 2001) Excess weight gain may independently predisposeand portend risk for subsequent reproductive endocrine and metabolic dis-orders Various theories have been offered to explain this higher prevalence

dis-of PCOS and other reproductive disorders in these patient populations, cluding the effects of the disease itself and of antiepileptic drugs, especiallyvalproate, which may directly cause PCOS or indirectly lead to the disorder

in-by causing weight gain that triggers insulin resistance, increased one levels, and other reproductive abnormalities

testoster-CLINICAL FEATURES

Hyperandrogenism and anovulation are the key features of PCOS, as fined by the National Institutes of Health (NIH) consensus diagnostic crite-ria The common clinical manifestations of these abnormalities, therefore,are as follows:

de-Menstrual Irregularities

These may manifest themselves at puberty either with delayed menarchefollowed by the onset of irregular periods or as the breakdown of a previ-ously regular menstrual cycle within a few years Chronic anovulation inPCOS is associated with disordered gonadotropin secretion and presents asoligomenorrhea (8–10 menstrual cycles/year) or amenorrhea (the absence

of menstrual cycles) before menopausal onset (Lobo & Carmina, 2000).Women with PCOS often are infertile, and for the few PCOS patients whobecome pregnant, there are increased risks of miscarriage, gestational dia-betes, and pregnancy-induced hypertension (Duncan, 2001; Lobo & Car-mina, 2000; Ernst, 2002)

These menstrual irregularities are also associated with weight gain,and it is reported that approximately half of the women with PCOS areobese and that 20% of them will have either impaired glucose tolerance ortype 2 diabetes by the time they reach 40 years of age (Duncan, 2001).Other risks associated with PCOS are endometrial hyperplasia or malig-nancy, hypertension, coronary heart disease, and unhealthy lipid profiles,that is, elevated levels of triglycerides and low-density lipoproteins (LDLs)

Hyperandrogenism

Hyperandrogenism may appear clinically as hirsutism, acne, male patternbalding, and/or male distribution of body hair or alopecia (Lobo &Carmina, 2000) The virilizing features of this illness are due to the elevatedandrogens (testosterone and androstenedione) and their precursors dehydro-epiandrosterone (DHEA) and dehydroepiandrosterone-sulfate (DHEAS;Herzog, 1996) The excess androgens are associated with subtle hyperes-trogenism (Lobo & Carmina, 2000; Dahlgren et al., 1992)

It is thought that the disorder may be caused by increased genic activity that is an intrinsic defect in the ovary (Dunaif & Thomas,

steroido-2001) In vitro studies show that women with PCOS secrete increased

amounts of androstenedione (an androgen) and increased amounts of hydroxyprogesterone (a steroid that is an intermediate in the androgen andglucocorticoid biosynthetic pathway) from thecal cells (the androgen-producing cells of the ovary) This increased secretion by thecal cells may

17-be a result of dysregulation of the rate-limiting enzyme in androgenbiosynthesis, cytochrome P-450c17α

Reproductive Endocrine Abnormalities

Reproductive endocrine abnormalities are often present, but none are onomonic or found in all women with the disorder The common endocrineabnormalities include: elevation of LH in urine and serum and low normal

path-plasma FSH, leading to an increased LH/FSH ratio (Duncan, 2001) This nadotropin hormonal imbalance leads to an increase in LH-stimulated ovar-ian steroidogenesis and a decrease in follicle maturation (Franks, Mason, &Willis, 2000; Rasgon, 2004) This incomplete follicle maturation in turn isthought to lead to the formation of a larger number of small, immature folli-cles and, subsequently, the formation of follicular cysts (Rasgon, 2004).Furthermore, decreases in SHBG as a result of hyperinsulinemia andhyperandrogenism, are commonly seen in this syndrome The decreasedSHBG concentration increases the bioavailable fraction of androgens andestrogens, which may increase free testosterone levels In general, however,estrogen and FSH levels remain in the normal range (Isojärvi et al., 1995;Bauer et al., 2000; Herzog, 1996).

go-Metabolic Abnormalities

Metabolic abnormalities such as hyperinsulinemia and insulin resistanceoccur at greater frequency and intensity in women with PCOS Approxi-mately 40% of women with PCOS have been shown to have impaired glu-cose tolerance tests (Ehrmann et al., 1999; Legro et al., 1999) The rates ofimpaired glucose tolerance vary from 31 to 35%, versus 7.8% when com-pared with the general U.S female population (Ehrmann et al., 1999; Legro

et al., 1999) Consequently, up to 20% of obese women may exhibit type 2diabetes by age 40 years (Dunaif, 1995) Insulin resistance is independent

of the effect of obesity and may occur regardless of whether the women arelean or obese compared with normal women (Franks, 1995) Further, Loboand Carmina (2000) have shown that insulin resistance has been found to

be more pronounced in women with chronic anovulation than in thosewho have ovulatory cycles

In women with PCOS, insulin resistance is characterized by decreasedsensitivity to insulin in peripheral tissues but not hepatic resistance, unlikeinsulin resistance in type 2 diabetes Hopkinson and colleagues (1998) re-ported that there was support for suggesting that decreased peripheral insu-lin sensitivity and, consequently, hyperinsulinemia were pivotal to thepathogenesis of PCOS Hopkinson hypothesized that insulin acts in theliver to inhibit the production of insulin-like growth factor 1 (IGF-1) bindingprotein and SHBG, with the latter leading to an increase in free testoster-one Therefore, according to Hopkinson, insulin resistance not only in-creases the secretion of ovarian androgen but also promotes an increase inthe proportion of free (biologically active) hormone

Lipid and Lipoprotein Abnormalities

These abnormalities include elevated LDLs and triglycerides, decreased els of high-density lipoproteins (HDL), and apolipoproteins A-1 (Legro,

lev-Kunselman, & Dunaif, 2001; Lobo & Carmina, 2000) Additionally, paired fibrinolytic activity has also been reported, as assessed by measure-ments of elevated levels of circulating plasminogen activator inhibitor levels(a potent inhibitor of fibrinolysis), which has been shown to be a risk factorfor the occurrence of hypertension and myocardial infarction (Dahlgren etal., 1992; Hopkinson et al., 1998) However, decreased levels of HDL isconsidered to be the most characteristic lipid abnormality in women withPCOS (Hopkinson et al., 1998).

im-Reproductive Abnormalities

These abnormalities can often develop shortly after menarche in manywomen and can last most of their reproductive lives In others it may ap-pear as a breakdown of a previously regular menstrual cycle, which is oftenassociated with weight gain (Duncan, 2001) However, the most pressingconcern is the occurrence of varying degrees of infertility, with PCOS iden-tified in 75% of women with anovulatory infertility (Legro et al., 2001).Women have also been reported to be at much greater risk of having multi-ple pregnancies through ovulation induction or after in vitro fertilization(Legro et al., 2001)

ETIOLOGY

The etiology of PCOS is not fully understood, though several authors havesuggested that PCOS is caused by interactions between a variety of genetic,neuroendocrine, metabolic, and environmental factors (Rasgon, 2004;Dunaif & Thomas, 2001)

Genetic Factors

Familial aggregation of PCOS has been clearly established, suggesting netic susceptibility (Franks, 1995; Legro & Strauss et al., 1998) Variousmodes of transmission have been discussed, including an autosomal domi-nant inheritance pattern based on familial aggregation of hyperandro-genism in first-degree relatives of patients with PCOS (Legro, Strauss, et al.,1998; Ernst & Goldberg, 2002) In addition, brothers of women withPCOS often show evidence of insulin resistance and elevated dehydroepian-drosterone levels, findings that might suggest their reproductive and meta-bolic phenotypes resemble those of their sisters with PCOS (Dunaif &Thomas, 2001) There is also evidence that there may be a genetic defect inovarian and adrenal androgen biosynthesis that may synergize with a meta-bolic abnormality (Rasgon, 2004; Lobo & Carmina, 2000) Studies onwomen with PCOS suggest that the disorder may be caused by increased

ge-steroidogenic activity that is intrinsic, presumably a genetic defect in the

ovary (Dunaif & Thomas, 2001) In vitro studies have shown that women

with PCOS secrete increased amounts of androstenedione (an adrogen) and17-hydroxyprogesterone (a steroid that is an intermediate in the androgenand glucocorticoid biosynthetic pathway) from thecal cells (the androgenproducing cells of the ovary) This increased secretion by thecal cells may

be a result of dysregulation of the rate-limiting enzyme in androgenbiosynthesis, cytochrome P-450c17a (Franks, 1995)

In order to determine whether there was a biochemical reproductiveendocrine phenotype, Legro, Spielman, et al (1998) studied the sisters ofwomen with PCOS and found that there was familial aggregation ofhyperandrogenemia in PCOS kindreds, with 46% of 115 sisters thus af-fected Only one-half of these sisters fulfilled diagnostic criteria for PCOSwith chronic anovulation and hyperandrogenemia The remaining affectedsisters had hyperandrogenemia with regular menses The affected sistersalso had a significant elevation of DHEAS levels, suggesting that there was

an adrenal component to the hyperandrogenemia The distribution of tosterone levels in the sisters appeared to be bimodal Although the samplesize was relatively small, this suggested that testosterone levels in PCOSfamilies reflected a monogenic trait controlled by two alleles at an auto-somal locus

tes-A genetic defect may be responsible for the insulin resistance found inwomen with PCOS (Ernst & Goldberg, 2002) Defects in insulin receptorshave been reported in up to half of women with PCOS who also may have

a decrease in tyrosine phosphorylation and an increase in serine ylation These factors can all contribute to impaired insulin activity(Dunaif, 1995)

phosphor-Neurological Factors

The incidence of menstrual irregularities and PCOS both appear to be morecommon among women with epilepsy than among women without epi-lepsy (Bilo et al., 1988) PCOS has been reported to occur in 20% ofwomen with temporal lobe epilepsy and 25% of women with complex par-tial seizures (Herzog et al., 1986) Another study described PCOS in 15%

of women with primary generalized epilepsy (Bilo et al., 2001) In general,

it has been reported that PCOS occurs in 10.5–26% of women with lepsy (Bauer et al., 2000; Bilo et al., 2001) Some authors have suggestedthat epilepsy may play an intrinsic role in the development of PCOS(Herzog et al., 1986; Ernst & Goldberg, 2002) and postulate that epilepticdischarges from the amygdala to the hippocampus may affect the secretion

epi-of gonadotropin-releasing hormone (GnRH) Increased GnRH pulse quency in turn promotes LH secretion over FSH secretion and leads to anelevated LH/FSH ratio (Knobil, 1980)

fre-Furthermore, studies have demonstrated higher LH pulse frequencieswith left-sided than with right-sided temporal foci (Drislane et al., 1994),and PCOS may be more common with left temporolimbic epileptiform dis-charges than with right temporolimbic epileptiform discharges In turn,anovulatory cycles can trigger limbic seizure discharges (Herzog, 1993).Levels of progesterone, a hormone that can raise the seizure threshold, arelow in anovulatory women, including those with PCOS (Herzog et al.,1986) Therefore, it is postulated that temporolimbic structures in anovula-tory women are primarily exposed to estrogen, which has a knownproseizure effect In addition, limbic seizure discharges may also reduce lev-els of serum dopamine, leading to increased LH and prolactin secretion bythe pituitary (Herzog et al., 1986; Ernst & Goldberg, 2002) Alternatively,

a dysfunction in neurotransmission or genetic vulnerability common toboth epilepsy and reproductive endocrine disorders may account for thelink between PCOS and epilepsy (Herzog et al., 1986; Ernst & Goldberg,2002)

Endocrine Factors

The possible endocrine factors that may contribute to the development ofPCOS include an increased LH/FSH ratio and increased insulin and andro-gen concentrations Increased levels of 17-hydroxyprogesterone levels inthecal cells have also been implicated in playing a role in the development

of PCOS Abbott, Dumesic, and Franks (2002) propose a developmentaltheory in understanding some of these endocrine etiological factors Ac-cordingly, they postulated that during gestation, placental human chorionicgonadotrophin (hCG), fetal pituitary LH, and genes regulating folliculo-genesis and steroidogenesis, individually or together, result in fetal ovarianhyperandrogenemia that leads to prenatal, and possibly prepubertal, expo-sure to excess androgen Postpubertally, this early exposure to excessandrogen diminishes steroid hormone negative feedback on pituitary LH,resulting in abnormal LH secretion and predisposing women to accumula-tion of abdominal adiposity that exaggerates insulin resistance The result-ing hyperinsulinemia interacts with LH hypersecretion to augment ovariansteroidogenesis and to induce premature arrest of the follicle developmentand anovulation

Metabolic Factors

The insulin resistance that has been described in patients with PCOS creases the release of SHBG in the liver, which in turn increases free andro-gen levels that have been implicated in PCOS (Duncan, 2001) When pres-ent, obesity worsens insulin resistance (Dunaif & Thomas, 2001) furthermaking the patients more vulnerable to develop PCOS by the mechanism

de-described herein, as obesity independently is associated with decreased els of SHBG and elevated estrogen levels (Ernst & Goldberg, 2002).Research has shown that experimentally raising insulin levels can directlystimulate ovarian androgen production in women with PCOS (Dunaif &Thomas, 2001) Insulin can also stimulate steroidogenesis by enhancing thesensitivity to adrenocorticotropic hormone and thereby increasing pituitary

lev-LH release These reproductive effects of insulin appear to be limited towomen with PCOS It is important to note that insulin-lowering therapiescan restore menstrual cycles in some chronically anovulatory women withPCOS (Dunaif & Thomas, 2001)

Environmental Factors

A number of investigators have recognized that PCOS-like symptoms may

be manifested in response to environmental cues, such as prenatal exposure

to androgens and weight gain (Adams et al., 1985; Adams et al., 1986).Further, anabolic steroids and antiepileptic drugs (AEDs) have also beenimplicated in the development of PCOS Investigators have reported an in-creased frequency of reproductive disorders in patients with epilepsy(Franks, 1995; Wang, Davies, & Norman, 2001) Thus it is also possiblethat this population of patients is more likely to be treated with valproate,and, as a consequence, investigators observed a higher incidence of PCOS-like symptoms However, the finding that valproate increases steroidbiosynthesis in theca cells isolated from both normal-cycling and PCOS pa-tients suggests that valproate treatment could independently induce PCOS-like symptoms in the absence of a genetic predisposition for PCOS (Herzog

& Schachter, 2001; Ernst & Goldberg, 2002)

CORRELATION BETWEEN BIPOLAR

DISORDER AND PCOS

Reproductive disorders have also been reported to have an increasedprevalence in women with bipolar disorder Similar to epilepsy, contro-versy exists as to whether these abnormalities are caused by the bipolardisorder or by treatment (Rasgon et al., 2000; O’Donovan et al., 2002).The high rate of reported menstrual disturbances may indicate a preexist-ing compromise in reproductive endocrine function in women with bipo-lar disorder This preexisting potential compromise, in turn, may be amarker for dysregulation of the hypothalamic–pituitary–gonadal (HPG)axis Matsunaga and Sarai (1993) evaluated the HPG axis in 12 womenwith bipolar disorder They reported elevated basal LH in 8 women anddecreased basal FSH in 6 women Polycystic ovaries were observed byultrasonography in 8 of 12 cases, suggesting that a relationship might ex-

ist between bipolar disorder and the PCOS-associated hormonal malities in these cases In a study by Rasgon et al (2005), 80 womenages 18–45 years being treated for bipolar disorder and not taking ste-roid contraceptives were recruited to complete questionnaires about theirmenstrual cycles and to provide blood samples for measurement for arange of reproductive endocrine and metabolic hormone levels All womenreceived antimanic medications for bipolar disorder The investigators re-ported that 50% of women reported current menstrual abnormalities thatpreceded the diagnosis of bipolar disorder Fifteen percent reported devel-oping menstrual abnormalities since treatment for bipolar disorder, ofwhich 80% reported changes in menstrual flow (heavy or prolongedbleeding) and 33% reported changes in cycle frequency These resultswere consistent with an earlier report by Rasgon and colleagues (2000)indicating that menstrual abnormalities are common in women with bi-polar disorder and that the HPG axis may be compromised in somewomen with bipolar disorder In the latter study the participants receivedantimanic medications, and 35% also were taking oral contraceptives.Although it is possible that long menstrual cycles resulted from the phar-macological treatment of bipolar disorder, the observations that men-strual abnormalities precede the onset of bipolar symptoms and that si-multaneous oral contraceptive use is associated with long menstrualcycles suggest that women with bipolar disorder may have an underlyingpredisposition to long or abnormal menstrual cycles (Matsunaga & Sarai,1993; Rasgon et al., 2000) A recent study examined 300 women ages18–45 years with bipolar disorder who were evaluated for PCOS A compari-son was made between the incidence of hyperandrogenism and oligomen-orrhea that developed while taking valproate versus other anticonvulsants(lamotrigine, topiramate, gabapentin, carbamaxepine, and oxcarbaze-pine) and also lithium Of the 230 women who completed the evalua-tion, results showed that hyperandrogenism with oligomenorrhea developed

abnor-in 9 (10.5%) of 86 women on valproate and 2 (1.4%) of 144 women on

a nonvalproate anticonvulsant or lithium (relative risk 7.5%; p = 002).

Oligomenorrhea always began within 12 months of valproate use (Joffe

et al., 2006)

Others have suggested screening for bipolar disorder in women withPCOS In a pilot study of 78 women identified with PCOS, Klipstein andGoldberg (2006) reported that 28% had either been previously diagnosedwith bipolar disorder or had met Mood Disorder Questionnaire (MDQ)threshold criteria for bipolar disorder These authors concluded that there

is likely a higher rate of women with PCOS who screen positive for bipolardisorder than is expected in the general population Further, they postu-lated that there could be a link between PCOS and bipolar disorder second-ary to a possible shared HPG axis abnormality

CORRELATION BETWEEN ANTIEPILEPTIC

DRUGS AND PCOS

In Patients with Epilepsy

It has been suggested that use of anticonvulsants in general and sodiumvalproate in particular leads to an increased incidence of polycystic ova-ries and PCOS (Isojärvi et al., 1993; Isojärvi et al., 1995; Isojärvi et al.,1996; Isojärvi et al., 1998) In their initial study of 238 women with epi-lepsy, Isojärvi and colleagues (1993) reported some symptoms of PCOS

in 96 women, such as irregular menstrual cycles and hyperandrogenism,although the criteria used were not as defined by the NIH Twenty-nine(12%) were treated with valproate alone, 120 (50%) with carbamazepinealone, and 12 (5%) with a combination of valproate and carbamazepine;

62 (26%) were treated with other AEDs; and 15 (6%) received no cation Menstrual irregularities were reported by 45% of women receiv-ing valproate, by 19% of those receiving carbamazepine, by 25% ofthose receiving a combination of both, by 13% receiving other medica-tions, and by none who were untreated Results of vaginal ultrasono-graphy completed on the 96 women with histories of menstrual irregular-ities and epilepsy revealed polycystic ovaries in 43% of those treated withvalproate, in 22% of those treated with carbamazepine, and in 50% ofthe combination group

medi-In a subsequent study, Isojärvi et al (1995) studied 8 women with lepsy before and after 1 and 5 years of carbamazepine treatment All of thewomen had regular menstrual cycles before the study Of these 8 women, 2reported menstrual irregularities, and 3, including these 2 women, had ele-vated SHBG levels after 5 years of carbamazepine therapy

epi-In a 1996 study, Isojärvi et al compared 22 women with epilepsy ceiving valproate monotherapy, 43 women receiving carbamazepine mono-therapy, and a normal control group without epilepsy Polycystic ovaries,hyperandrogenism, or both were found in 64% of the valproate group,21% of the carbamazepine group, and 19% of the control participants.Further, polycystic ovaries and hyperandrogenism occurred more often inobese women on valproate (about 40%) than in lean women on valproate(about 20%) These women also had slightly higher fasting insulin levels(valproate-treated group, 16.9 ± 10.5; carbamazepine group, 15.4 ± 10.5;control group, 9.6 ± 5.1) The investigators also reported that half of thevalproate-treated group had progressive weight gain (mean = 21 kg) andlower insulin-like growth factor binding protein levels (Duncan, 2001).This weight gain is thought to perhaps lead to the development of the meta-bolic syndrome, including hyperinsulinemia, which has been shown tostimulate polycystic ovaries and androgen synthesis The diagnostic criteriaused in the preceding two studies did not meet NIH criteria, and no distinc-

re-tion was made by the authors between polycystic ovaries and PCOS No formation was available about ovarian structure and function prior totreatment with AEDs.

in-To examine whether discontinuing valproate would reverse its ent effects on weight, menstrual irregularities, frequency of polycystic ova-ries, testosterone levels, HDL-C, and triglycerides, Isojärvi et al (1998)studied 16 women with epilepsy who had polycystic ovaries or hyperandro-genism and were obese and who were switched to lamotrigine Over thenext year, 12 women who remained in the study lost weight, decreasedtheir waist and hip circumference, and showed a decrease in their bodymass index (BMI) In addition, insulin and testosterone levels decreased,and the lipid profiles improved Ultrasonography revealed that the number

appar-of follicles per ovary decreased and the number appar-of women who had strual abnormalities decreased The small sample size, lack of controlgroup, selection of only obese women, and nonrandomization were amongthe limitations of this study

men-In a larger cohort of women with epilepsy being treated with eithervalproate or carbamazepine, Isojärvi et al (2001) further assessed the fre-quency of metabolic and reproductive endocrine disorders The authorsstudied 72 women and noted that neither the duration of epilepsy, treat-ment with valproate, nor dose was associated with polycystic ovaries orhyperandrogenism Similar to their previous study (Isojärvi et al., 1996),polycystic ovaries and hyperandrogenism were seen in 79% of obesewomen and 65% of lean women treated with valproate This informationwas not reported for the carbamazapine group or control group The fre-quency of polycystic ovaries and hyperandrogenism in the carbamazepine-treated group was 20% and, among the normal controls, 19% Menstrualdisorders were seen in 79% of the obese valproate-treated women and in48% of the lean valproate-treated women, in comparison with 13% of theobese control participants and 17% of the lean control participants whohad menstrual irregularities This information was not reported for thecarbamazepine-treated women, though this group had a slightly lower fre-quency of menstrual disorders than controls The authors also did not re-port separate hormone values for lean or obese carbamazepine-treated orcontrol-group participants

Compared with controls in the same study, women on valproate hadhigher testosterone levels and lower ratios of HDL-C to total cholesterol

As expected, obese valproate-treated women had higher BMI, higher lin, and higher lipid profiles and lower HDL-C to total cholesterol ratiosthan the lean valproate-treated women However, the contribution ofvalproate versus obesity to metabolic and hormonal abnormalities in thissample was unclear as only 14 (38%) of 37 women taking valproate wereobese Furthermore, LH levels in valproate-treated women were not signifi-cantly different from those of the control group Although at first glance

insu-these data appear to support the hypothesis that the metabolic ties induced by valproate may contribute to the development of the symp-toms of PCOS, it is difficult to make generalizations because of the studydesign and unreported data sets The effects of obesity versus those ofAEDs on the development of polycystic ovaries and hyperandrogenismneed to be studied independently.

abnormali-Several other investigators have conducted studies to replicate the ings reported by Isojärvi and colleagues Pylvanen et al (2002) demon-strated that the rates of obesity were the same in patients with epilepsy tak-ing valproate as in normal control participants However, both lean andobese patients receiving valproate had higher insulin levels than controls,but there was no difference in leptin levels between any of the groups In re-viewing this study, Rasgon (2004) concluded that these data support acausative role for valproate rather than obesity in the development ofhyperinsulinemia and suggest that valproate may be directly linked to insulin-stimulated hyperandrogenism in women with epilepsy However, it is im-portant to note that no untreated patients with epilepsy were included inthe study, and the effect of epilepsy on hyperinsulinemia could not be inde-pendently assessed (Rasgon, 2004)

find-It can be argued that early exposure to valproate may increase the risk

of PCOS secondary to earlier changes in cellular mechanisms that arethought to be the potential mechanisms for valproate dependent changesthat can have an effect on follicular development in the young ovaries ofdeveloping girls Because increased androgen production is a stable pheno-type of PCOS theca cells, it is possible that the earlier these biochemicaland perhaps structural changes occur, the more irreversible they may be,leading to a greater susceptibility and risk for the development of PCOSsecondary to valproate treatment

In another study examining the effects of AEDs in women with andwithout epilepsy, Betts, Yarrow, Dutton, Greenhill, and Rolfe (2003) stud-ied 105 women, 54 of whom had been treated only with valproate and 51

of whom had either been treated with lamotrigine or carbamazepine for atleast 1 year They were compared with 50 women without epilepsy Mea-surements of FSH, LH, testosterone, and prolactin were obtained fromdays 2 to 6 of their menstrual cycle, along with magnetic resonance image(MRI) scans of their pelvises Women with epilepsy in general were signifi-cantly more likely to exhibit polycystic ovaries on their scans Women tak-ing valproate but not an oral contraceptive were also significantly morelikely to have clinical biochemical evidence of PCOS with raised LH and/ortestosterone than women who did not have epilepsy This was not the casewith women on either lamotrigine or carbamazepine The investigatorsconcluded that women with epilepsy—particularly if they are not takingoral contraceptives—are more likely than those without epilepsy to havepolycystic ovaries by the European definition Second, they concluded that

women with epilepsy who are not taking oral contraceptives are cantly more likely to have PCOS if they have ever taken valproate (but not

signifi-lamotrigine or carbamazepine; p = 003) Based on this finding, they

sug-gested that perhaps oral contraceptives protect against polycystic ovaries inwomen who take valproate as an anticonvulsant They reason that this in-creased risk with valproate is due to valproate being the only anticonvul-sant to be associated with an increase in insulin resistance, which is one ofthe many factors to be associated with polycystic ovaries Betts et al (2003)recommended that valproate should be avoided in women of childbearingage

Murialdo et al (1997) studied 101 women with epilepsy between theages of 16 and 50 years who were treated with a number of different AEDsthat included phenobarbitol, phenytoin, and primidone, in addition tovalproate and carbamazepine They reported the occurrence of polycysticovaries in 12% of the phenobarbitol group; 21% of the carbamazepinegroup; 0% of the valproate group; 40% of those receiving polytherapy thatincluded valproate; and 13% of the group receiving polytherapy that didnot include valproate None of the women with polycystic ovaries exhib-ited any PCOS A subsequent study by the same investigators (Murialdo etal., 1998) of 65 women with epilepsy being treated with valproate,carbamazepine, or phenobarbitol reported that the rates of polycystic ova-ries, ovary volume, and hirsutism did not differ significantly among thethree treatment groups

In a study of 50 women with various forms of epilepsy, Bilo et al.(2001) found no significant association between reproductive endocrinedisorders such as PCOS, hypothalamic amenorrhea, and luteal phasedeficiency based on epilepsy type or AED treatment with or withoutvalproate They concluded that PCOS preceded the use of any AEDs andwas increased in women with epilepsy independent of any drug treatmenteffects

In an international multicenter study, 222 women with epilepsy of productive age were examined for the presence of menstrual irregularitiesand endocrine changes related to treatment with AEDs Their resultsshowed that although testosterone levels were within normal range forboth groups (valproate or lamotrigine monotherapy), they were somewhathigher in the valproate group On the other hand, total cholesterol andLDL levels were lower in the valproate group, and there was no difference

re-in the re-insulre-in levels (Taylor, 2001)

Similarly, Bauer et al (2000), in a prospective study, found no tion between PCOS and valproate or carbamazapine treatment in a study

associa-of 93 women with epilepsy, refuting the earlier results associa-of Isojärvi and leagues (1993; Isojärvi et al., 1995; Isojärvi et al., 1996; Isojärvi et al.,1998) In this study the diagnosis of PCOS was made using the NIH criteriaand hence distinguished between polycystic ovaries and PCOS Compari-

col-sons were made between four groups of women: untreated, valproatetreated, carbamazepine treated, and polytherapy treated.

In a longer term study following 43 women with epilepsy for 3 years

who were being treated with valproate (n = 22), lamotrigine, or zepine (n = 21), Luef, Abraham, Trink, et al (2002) also found no associa-

carbama-tion between valproate treatment and the frequency of menstrual disorders,polycystic ovaries, or both However, they did report increased androgenlevels in women on valproate A larger study of 105 women with epilepsy,completed by the same authors (Luef, Abraham, Trinka, et al., 2002), alsoreaffirmed the findings reported in the earlier study Patients in this study

treated with valproate (n = 52) had a slightly lower incidence of menstrual

disturbance (11%) and polycystic ovaries (12%) than those treated with

carbamazepine (n = 53; 16% and 14%, respectively) These differences

were not found to be significant The rate of incidence of polycystic ovaries

in the patients was 27%, compared with the rate of 20–30% in the generalpopulation, indicating no increase in the incidence of polycystic ovarieswith valproate treatment

Examining the relationship between ovulatory function and treatmentwith AEDs, Morrell et al (2002) conducted a study on 94 women with epi-lepsy and 23 controls The AEDs used were carbamazepine, valproate,phenytoin, phenobarbitol, lamotrigine, or gabapentine as monotherapy for

6 months or more There were no statistically significant differences in thefrequency of polycystic ovaries between any of the AED treatment groups.However, women with epilepsy were more likely to be obese than the con-trols, and obesity was higher in patients receiving valproate or lamotrigine.The authors acknowledged, however, that they were unable to control forprevious use of AEDs prior to 6 months or for medication change and thatthe numbers of participants in any of the AED groups were variable, be-cause the AED was selected based on the type of seizure

A year later Morrell and colleagues (2003) published the results of anopen-label, cross-sectional multicenter study of 198 women under the age

of 35 years with a history of epilepsy who had been menstruating for atleast 4 years and had been treated with lamotrigine or valproate for at least

8 months but no more than 60 months and who were not taking oral

con-traceptives (lamotrigine, n = 106; valproate, n = 92) Their results showed

that compared with lamotrigine monotherapy, valproate monotherapy wasassociated with weight gain and higher androgen levels, hyperandrogenism,and longer menstrual cycles that were less likely to be regular, suggestingthat these endocrine changes observed in some women using valproate forepilepsy may be secondary to drug therapy

There is a paucity of studies examining the long-term reproductive docrine health of young women with epilepsy during puberty Little isknown about the long-term effects of the use of AEDs during childhoodand adolescence on reproductive endocrine health Mikkonen et al (2004)

en-studied 69 patients and 51 control participants over a period of time Atentry to the study, the age range was 8–18.5 years, and at follow-up, 12.5–25.8 years Initially 35 patients were taking valproate, 17, carbamazepine,and 17, oxcarbazepine, as monotherapy At follow-up only 42 of the 69 pa-tients were on medications All the participants were examined clinically,medical and menstrual histories were obtained, ovarian ultrasonographywas examined, and serum reproductive hormone concentrations were ana-lyzed The results revealed no significant differences in laboratory or clini-cal findings between patients off medication and the controls Postpubertalpatients still on medication had higher serum testosterone and androsten-edione levels than patients off medication, All the patients still on valproatehad elevated serum androstenedione levels PCOS was more common in38% of the patients on medication (63% on valproate, 25% on other

AEDs) than in patients off medication (6%) or in controls (11%; p =

.0005) The investigators concluded that epilepsy during pubertal tion does not affect reproductive endocrine health in participants who dis-continue the medication before adulthood However, an increased preva-lence of endocrine disorders is detected if the patients remain on AEDs,especially valproate, until adulthood

matura-In an attempt to resolve the controversy and difficulty in separatingmenstrual and metabolic disturbances in women with epilepsy from effects

of the AEDs, Ferin et al (2003) studied the endocrine and metabolic sponse to long-term therapy with valproate on the normally cycling rhesusmonkey They compared two groups of 7 monkeys in each group, one free

re-of medication and the other receiving valproate for a duration re-of 12.7–15.7months The results showed no difference in testosterone or LH levels be-tween the two groups; both groups also had similar glucose and insulin re-sponses to a glucose tolerance test Examination of all 14 ovaries showed

no histological evidence of PCOS The investigators concluded that their sults “did not support the hypothesis that treatment with valproate per se isresponsible for the induction of PCOS” (Ferin et al., 2003, p 2915)

re-In contrast, Nelson-DeGrave et al (2004) published a study reportingthat valproate potentiates androgen biosynthesis in human ovarian thecacells The theca cells were isolated from follicles of normal-cycling women.The cells were treated for 72 hours with sodium valproate Whereas lowdoses (i.e., 30–300 ug) had no effect on basal and forskolin-stimulated pro-gesterone production, higher doses (1000–3000 ug) inhibited progesteroneproduction The most pronounced effect of valproate on androgen biosyn-thesis was observed in the dose range of 300–3000 ug, which representstherapeutic levels in the treatment of epilepsy and bipolar disorder Theinvestigators reported that valproate increased both basal and forskolin-stimulated P459c17 and P450scc protein levels, whereas the amount ofsteroidogenic acute regulatory protein was unaffected Consistent with theability of valproate to act as a histone deacetylase (HDAC) inhibitor in

other cell systems, valproate (500µg) treatment was observed to increasehistone H3 acetylation and P450 17 alpha-hyroxylase mRNA accumula-

histone H3 acetylation and DHE biosynthesis, whereas valproate derivative

on histone acetylation of DHEA biosythesis The authors of this study cluded that these findings suggest that valproate-induced ovarian androgenbiosynthesis results from changes in chromatin modifications (histoneacetylation) that augment transcription of steroidogenic genes This is thefirst study of its kind to provide biochemical evidence to support the role ofvalproate in the genesis of PCOS-like symptoms and to establish a directlink between valproate and increased ovarian androgen biosynthesis

con-On the other hand, animal experiments have confirmed that in tients with unilateral amygdaloid seizures, the amygdala ipsilaterally acti-vates neurons in the medial preoptic area, ventrolateral part of theventromedial area, and premammillary nuclei of the hypothalamus, areasthat are specifically involved in reproductive neuroendocrine function(Silveira et al., 2000) Furthermore, induction of seizures in the amygdalaleads to a decrease in ipsilateral GnRH neuron fiber number (Friedman etal., 2002) These findings further support the hypothesis that unilaterallimbic seizures may modulate reproductive endocrine function in a laterallyasymmetric manner

pa-In Patients with Bipolar Disorder

Several investigators have also examined the occurrence of PCOS in tients with bipolar disorder (See Table 17.1) As is the case with patientswith epilepsy, with whom there is controversy about whether PCOS occursindependent of the treatment with AEDs, so is the case in patients with bi-polar disorders, with whom AEDs are often used as mood stabilizers totreat bipolar disorder Rasgon et al (2000) conducted a pilot study to de-termine whether PCOS is associated with valproate use in the treatment ofbipolar disorder The study evaluated the clinical and hormonal character-istics of PCOS in 22 women with DSM-IV diagnoses of bipolar disorderbetween the ages of 18 and 45 years None of the patients met the NIH cri-teria of PCOS at the beginning of the study Ten patients were receivinglithium monotherapy, another 10, valproate monotherapy, and 2, lithium-valproate combination therapy Patients had a mean exposure of 5 years tolithium, 3 years to valproate, and 1 year to combination therapy

pa-All patients on lithium monotherapy or combination therapy and 60%

of patients on valproate monotherapy reported menstrual disturbances ceding the start of medication, again suggesting that, as in the case of pa-tients with epilepsy, some women with bipolar disorder may have compro-mised HPG axis independent of therapeutic agents used There were no