Valproate and the Polycystic Ovarian Syndrome: Final Thoughts

This commentary addresses four issues: (a) What ispolycystic ovarian syndrome (PCOS)? (b) Is it particu-larly common among women with epilepsy? (c) Is PCOSattributable to epilepsy, valproate (VPA) use, both, orneither? And (d) Is there any practical significance to thisissue?WHAT IS POLYCYSTICOVARIAN SYNDROME?Polycystic ovarian syndrome (PCOS) is hyperandro-genic chronic anovulation, that is hyperandrogenismwith menstrual, ultrasound, or endocrine evidence of an-ovulatory cycles (1). Hyperandrogenism is representedby elevated serum levels of testosterone, androstenedi-one, or dehydroepiandrosterone in its free or conjugatedsulfated form. Hirsutism is also a characteristic feature,but its manifestation may vary considerably in relation toethnic origin, even in the presence of hyperandrogen-emia. Chronic anovulation is represented by (a) men-strual disorder (amenorrhea, oligomenorrhea, abnormalmenstrual cycle intervals, or menometrorrhagia), and of-ten by (b) ultrasound evidence of enlarged ovaries withmultiple follicular cysts and increased stroma, and (c)abnormally low serum progesterone levels during themidluteal phase. Affected women, however, commonlyrevert spontaneously to having fertile ovulatory cycles.There is no known single specific cause. PCOS is abona fide “syndrome” with multiple etiologies and con-tributory factors, including genetic (autosomal domi-nant), endocrine (ovary, adrenal), metabolic (obesity, in-sulin resistance), and neurologic (limbic, hypothalamic)causes. The broad definition of PCOS includes specificdiagnostic entities that many today consider separately,such as the nonclassic forms of heredofamilial adrenalhyperplasia, ovarian virilizing tumors, various identifi-able causes of hyperprolactinemia, and thyroid disorders.Our view is to include them under the rubric of thegeneral syndrome and then to classify PCOS as to spe-cific etiology or as idiopathic. Minimal criteria for des-ignation should establish the occurrence of hyperandro-genic chronic anovulation and exclude hyperandrogen-ism or polycystic ovaries with no other concomitants.IS PCOS PARTICULARLY COMMON AMONGWOMEN WITH EPILEPSY?The prevalence of PCOS in the general female popu-lation has been a matter of debate, with estimates rangingfrom as low as 3–4% to as high as 18–19%, dependingon the definitional parameters used and the populationstudied. Knockenhauer et al. (2) identified PCOS, con-sisting of hyperandrogenism (hyperandrogenemia and/orhirsutism) and oligomenorrhea, in 3–4% of women in ageneral community survey in the southeastern UnitedStates. Polson et al. (3) have reported polycystic ovaries(PCO) in 23% of a series of volunteers recruited amongBritish hospital employees. Three fourths of thesewomen (i.e., 18% overall) had menstrual disorders aswell, and most of the women with PCO were reported tohave either menstrual disorder, hirsutism, or both,thereby rating the designation of PCOS. Serum testos-terone levels in the women with PCO, however, weresimilar to those of women with normal ovaries. Claytonet al. (4) identified a similar proportion of women ashaving PCO, specifically 22%, but only 30% of themexhibited menstrual disorders, and only 14% had hirsut-ism, again without a significant difference in serum tes-tosterone levels. This series suggests that PCOS occurredin ∼6.6% of women. In our most recent control series ofwomen of reproductive age, between 18 and 45 years (5),we have identified menstrual disorders (defined as amen-orrhea, no menses for 6 months; oligomenorrhea, >32-day intervals; polymenorrhea, 4 days’ variability in interval; or menome-trorrhagia, heavy menses and bleeding between periods)in 10% of 100 women in a primary care physician’scommunity practice and 14% of 100 women who see agynecologist in a teaching hospital setting. The combi-nation of PCOS characteristics (i.e., hirsutism and men-