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Polycystic ovary syndrome--"A riddle wrapped in a mystery inside an enigma".

Among the infertility disorders, polycystic ovary syndrome (PCOS) is one of the most common, affecting approximately 4 million U.S. women and more than 100 million women worldwide. Excluding PCOS-associated morbidities in menopause, the economic burden of PCOS exceeds several billion dollars annually in the United States. PCOS is characterized by both reproductive and metabolic dysfunctions with familial clustering. From a reproductive perspective, women with PCOS are characterized by hyperandrogenism, polycystic ovaries, LH hypersecretion, and reduced fecundity. Women with PCOS are also at risk for ovarian hyperstimulation/multiple gestations in response to fertility treatments and are more likely to develop gestational diabetes and preeclampsia (1). Most women with PCOS also manifest insulin resistance and -cell dysfunction (2). PCOS is viewed by some as a clinical phenotype of the metabolic syndrome (3). An estimated 10% of women with PCOS develop type 2 diabetes. Like most prediabetic states, PCOS is associated with an increased risk of cardiovascular disease, dyslipidemia, hypertension, and endometrial cancer (4). This emphasizes the longterm need for prevention of diabetes mellitus, heart disease, and cancer in this population. More importantly, a concern is that both metabolic and reproductive consequences of PCOS may not stop with the patient. The emerging field of epigenetics suggests that altered metabolism in mothers creates an unfavorable environment for the fetus, thus greatly enhancing the likelihood of diseases in the offspring (5). If so, women with PCOS visiting fertility clinics may have children who manifest metabolic and reproductive perturbations, many of whom could subsequently develop PCOS. Studies described in this issue of JCEM by Sir-Petermann et al. (6) focusing on the reproductive and metabolic phenotype of female offspring of women with PCOS is of relevance for several reasons. First, the study describes the potential for heritability of metabolic and reproductive perturbations in the offspring of women with PCOS. Second, it addresses the timing and sequence of the onset of metabolic and reproductive perturbations in the offspring, a critical gap in determining type and timing of therapeutic interventions. Central to this aspect of the study is also the “chicken or the egg” aspect of PCOS, namely, whether hyperinsulinemia precedes hyperandrogenism or vice versa. Finally, the findings are of global relevance in relating the contributory role of the maternal environment to the development of the disease state in the offspring. Addressing early defects in the offspring of women with PCOS is an essential first step for developing appropriate interventions to mitigate progression of these early metabolic and reproductive disruptions in these offspring into PCOS. The etiology of PCOS is unknown, although both genetic and environmental factors have been implicated (7). Despite the shortcomings, family studies of PCOS have consistently indicated familial clustering in first-degree relatives of PCOS subjects and point to an underlying genetic component (8). Familial clustering of hyperandrogenemia is the strongest evidence of a genetically inherited trait in first-degree relatives of PCOS women (9). Other familial studies also support clustering of PCOS symptoms such as polycystic ovaries, clinical hyperandrogenism, as well as hyperinsulinemia and insulin resistance (10). Twin studies demonstrate a higher prevalence of PCOS symptoms in monozygotic compared with dizygotic twins (11), providing strong support for a genetic component. Although siblings of affected women are at a higher risk, PCOS does not exhibit a clear Mendelian pattern of inheritance. Efforts to elucidate the genetic basis of PCOS have relied largely on a candidate gene approach focusing on relevant pathways, such as steroid synthesis or insulin signaling. Although several loci have been proposed, to date, no gene has been clearly implicated in the development of a PCOS phenotype. Failure to replicate positive results in these studies appears to relate to lack of a universally accepted diagnostic criteria for PCOS (12) and incomplete knowledge of the pathophysiology of PCOS. Linkage studies within PCOS families point to a possible association in chromosome 19p13.2 (8). An emerging pattern of inheritance supports gene environment interactions — a model that would account for the