Jon Havelock, MD, FRCSC Polycystic ovary syndrome Therapy for this reproductive and metabolic disorder remains focused on managing symptoms, including infertility caused by anovulation, and reducing long-term health risks such as endometrial cancer and type 2 diabetes. ABSTRACT: The clinical presenta- olycystic ovary syndrome drome was the term used for more tion of polycystic ovary syndrome is (PCOS) is a prevalent repro­ than 50 years for the heterogeneous widely variable, with complaints en- P ductive and metabolic disorder clinical features of the disorder now compassing oligomenorrhea, infer- with variable phenotypes and an under­ known as polycystic ovary syndrome. tility, obesity, hirsutism, endometrial lying pathophysiology that is still not In 1990 the first international defini­ cancer, and diabetes. Community completely understood. While the tion of PCOS was developed, which physicians caring for reproductive- earliest description of the polycystic has since been revised by various age women will invariably encounter ovary dates back to the 17th century,1 professional bodies. The lack of con­ this reproductive and metabolic dis- the characterization of the present­ sensus in the definition of PCOS fur­ order resulting from ovarian hyper- day disorder known as PCOS was first ther highlights the uncertainty about androgenism and insulin resistance. detailed by Irving Stein and Michael the pathophysiology of the disorder. While community physicians should Leventhal in 1935.2 In a seminal pa­ However, for the practising physician be aware of the diagnostic criteria per, the two prominent gynecologists a thorough understanding of symptom for polycystic ovary syndrome, it is described a case series of seven wom­ management and prevention of long­ more important to have a thorough en with enlarged ovaries associated term complications is more important understanding of symptom manage- with oligomenorrhea or amenorrhea, than an understanding of the different ment and prevention of long-term sterility, and clinical hyperandrogen­ diagnostic criteria for PCOS. complications. Historically, clo- ism. Histopathologic determination of miphene citrate has been used to the disorder was undertaken by wedge Pathophysiology address infertility by inducing ovu- biopsy of the ovaries. The surgical The abnormal findings in PCOS are a lation, with more recent evidence procedure that led to characterization result of ovarian hyperandrogenism3 supporting the use of letrozole as of the disorder also serendipitously first-line therapy for ovulation induc- led to the first therapeutic intervention Dr Havelock is a co-director of the Pacific tion. These and other mainstay treat- for infertile women with PCOS. Five Centre for Reproductive Medicine and a ments may be needed to address of the seven women subsequently clinical assistant professor in the Division anovulation, obesity, and hirsutism. conceived after normalization of their of Reproductive Endocrinology and Infer- Patients should also be monitored menstrual cycles. One woman who tility at the University of British Columbia. for endometrial cancer and type 2 did not conceive was affected by male He is also the former program director for diabetes. factor infertility and the other woman the subspecialty residency in Gynecologic was lost to follow­up. Reproductive Endocrinology and Infertility This article has been peer reviewed. As a result, Stein­Leventhal syn­ at UBC. 210 BC MEDICAL JOURNAL VOL. 60 NO. 4, MAY 2018 bcmj.org Polycystic ovary syndrome and insulin resistance.4 Evidence sug­ drogens, as demonstrated in the simi­ exclusion of other known disorders. gests that the ovarian hyperandrogen­ lar ultraosonographic findings and The National Institutes of Health ism in PCOS is a result of primary gene expression profile studies on the (NIH) conference on PCOS in 1990 ovarian dysfunction and is second­ ovaries of women with PCOS and the led to the first internationally accept­ ary to disordered gonadotropin activ­ ovaries of androgen­treated female­ ed diagnostic criteria. The two criteria ity. While not included in diagnostic to­male transgender individuals.9 (clinical and/or biochemical evidence criteria for PCOS, the elevated level Evidence for the role of insulin of hyperandrogenism and menstrual of serum luteinizing hormone (LH) resistance in the pathophysiology of dysfunction) were based on expert in affected patients due to inappro­ PCOS and ovarian hyperandrogen­ opinion solicited through a question­ priate secretion has long been recog­ ism is demonstrated indirectly by naire. In 2003 the Rotterdam criteria nized.5 LH is the ligand for the LH the findings of hyperandrogenism in developed by the European Society receptor on the ovarian theca cells female subjects with type A insulin of Human Reproduction and Embry­ responsible for ovarian androgen pro­ resistance syndrome, a disorder char­ ology and the American Society for duction. Genome­wide association acterized by a mutation in the insulin Reproductive Medicine (ESHRE/ studies conducted on hyperandro­ receptor gene.10 Insulin contributes to ASRM) allowed for the inclusion of genic subjects with PCOS revealed the biochemical and clinical hyperan­ polycystic­appearing ovaries on ul­ genome-wide significance for a locus drogenism by directly enhancing the­ trasound. This was defined as 12 or mapping to chr 11p14.1 in the region ca cell ovarian androgen production more follicles measuring 2 to 9 mm of the follicle­stimulating hormone in concert with LH,4 and indirectly in at least one ovary, or an ovarian beta polypeptide (FSHB).6 This sin­ by lowering sex hormone­binding volume greater than 10 mL in the gle­nucleotide polymorphism was globulin, the carrier protein respon­ absence of a dominant follicle. The associated with LH levels that result sible for reducing circulating free ESHRE/ASRM diagnostic guidelines in the elevated LH:FSH ratios often testosterone levels.11 The high preva­ only required meeting two of three seen in PCOS, providing further sup­ lence of impaired glucose tolerance criteria (clinical and/or biochemical port for the hypothesis that dysregu­ and type 2 diabetes in women with hyperandrogenism, oligomenorrhea lated gonadotropin secretion in PCOS PCOS has led researchers to consider and/or anovulation, and polycystic leads to secondary hyperandrogen­ the role of insulin sensitizers in treat­ ovaries).12 Most recently, the experts ism. This gonadotropin imbalance ing PCOS. contributing to the Androgen Excess favors an exaggerated intraovarian Society (AES) diagnostic guidelines androgen environment under the in­ Diagnostic criteria required meeting two criteria (clinical fluence of LH, and impaired follicu­ Three sets of diagnostic criteria for and/or biochemical hyperandrogen­ logenesis resulting in anovulation due polycystic ovary syndrome are used ism and either ovarian dysfunction or to a relative FSH deficiency. commonly ( Table 1 ). All require the polycystic ovaries).13 Evidence also suggests that the ovarian hyperandrogenism seen in PCOS is primary, with abnormal Table 1. Diagnostic criteria for polycystic ovary syndrome. ovarian steroidogenesis through over­ National Institutes of European Society for Human Androgen Excess Society expression of the CYP17 gene being Health criteria (1990) Reproduction and Embryology criteria (2006) responsible for androgen biosynthe­ • Must meet both criteria and American Society for • Must meet both criteria Reproductive Medicine Rotterdam sis, as well as increased expression criteria (2003) of the LH receptor, which would po­ • Must meet two of three criteria tentially render the ovarian theca cells Clinical and/or biochemical Clinical and/or biochemical Clinical and/or biochemical more sensitive to LH stimulation.7,8 evidence of evidence of hyperandrogenism evidence of The ovarian hyperandrogenism ap­ hyperandrogenism hyperandrogenism pears to play a role in the appearance Menstrual dysfunction Oligoovulation or anovulation Ovarian dysfunction or of the polycystic ovary on ultrasound polycystic ovaries and the follicular arrest and anovula­ Polycystic ovaries tion that is prevalent in PCOS. The Exclusion of other known Exclusion of other known disorders Exclusion of other known ovarian phenotype may result from disorders is required as is required as well. disorders is required as well. either endogenous or exogenous an­ well. BC MEDICAL JOURNAL VOL. 60 NO. 4, MAY 2018 bcmj.org 211 Polycystic ovary syndrome The Rotterdam criteria are the unit. Hirsutism is most commonly as­ the mid­luteal phase (day 21 to 23) of most widely used for PCOS diagnosis, sessed using the modified Ferriman- the menstrual cycle. If ovulation has and like the more liberal AES criteria Gallwey scale to quantify the amount occurred, the level will be 10 nmol/L they allow for different phenotypes of hair growth on various androgen­ or higher. of the disorder. Prevalence estimates dependent body areas. However, A diagnosis of PCOS rarely re­ for PCOS obtained using the Rotter­ race and ethnicity play a significant quires the use of ultrasound to con­ dam and AES criteria (12% to 18%) part in hirsutism.16 Additionally, the firm polycystic-appearing ovaries. As were up to twice that obtained using Ferriman­Gallwey scoring system symptom management is the focus in the NIH criteria (9%).14 NIH-defined can be somewhat impractical in ev­ PCOS, ultrasound adds little clinical PCOS is the most common pheno­ eryday clinical practice, and will be value. However, ultrasound may be type, and