Donna R. Chizen

Diagnostic Criteria for Polycystic Ovary Syndrome: Pitfalls and Controversies

It is estimated that as many as 1.4 million Canadian women may be afflicted with polycystic ovary syndrome (PCOS). Although PCOS is heralded as one of the most common endocrine disorders occurring in women, its diagnosis, management, and associated long-term health risks remain controversial. Historically, the combination of androgen excess and anovulation has been considered the hallmark of PCOS. To date, while these symptoms remain the most prevalent among PCOS patients, neither is considered an absolute requisite for the syndrome. Inclusion of ultrasonographic evidence of polycystic ovaries as a diagnostic marker has substantially broadened the phenotypic spectrum of PCOS, yet much debate surrounds the validity of these newly identified milder variants of the syndrome. Difficulty in resolving the spectrum of PCOS stems from the continued use of inconsistent and inaccurate methods of evaluating androgen excess, anovulation, and polycystic ovaries on ultrasound. At present, there is no clear-cut definition of biochemical hyperandrogenemia, particularly since we depend on poor laboratory standards for measuring androgens in women. Clinical signs of hyperandrogenism are ill-defined in women with PCOS, and the diagnosis of both hirsutism and polycystic ovarian morphology remains alarmingly subjective. Lastly, there is an inappropriate tendency to assign ovulatory status solely on the basis of menstrual cycle history or poorly timed endocrine measurements. In this review, we elaborate on these limitations and propose possible resolutions for clinical and research settings. By stimulating awareness of these limitations, we hope to generate a dialogue aimed at solidifying the evaluation of PCOS in Canadian women.

Prevalence of Polycystic Ovary Syndrome Phenotypes Using Updated Criteria for Polycystic Ovarian Morphology An Assessment of Over 100 Consecutive Women Self-reporting Features of Polycystic Ovary Syndrome

The prevalence of polycystic ovary syndrome (PCOS) and its distinct clinical phenotypes were assessed using 3 sets of international diagnostic criteria in women self-reporting concerns over outward features of PCOS. Revised ultrasonographic criteria for polycystic ovaries (PCO) based on modern ultrasound technology were used. Of the participants, 53%, 62%, and 70% were diagnosed with PCOS using National Institutes of Health, Androgen Excess and PCOS Society, and Rotterdam criteria, respectively. Prevalence of Frank, Ovulatory, Normoandrogenic, and Non-PCO PCOS were 66%, 13%, 11%, and 9%, respectively. Frank PCOS was associated with the severest metabolic disturbances whereas metabolic profiles in Normoandrogenic PCOS did not differ from controls, supporting reduced health risks in women without androgen excess. Metabolic disturbances and hyperandrogenism were linked to excess adiposity across all the groups. Using updated criteria for PCO, the prevalence of Non-PCO PCOS and PCO alone in healthy women recruited from the general population was reduced compared to the previous reports.

Detection of serum antimüllerian hormone in women approaching menopause using sensitive antimüllerian hormone enzyme-linked immunosorbent assays.

ObjectiveCurrent antimüllerian hormone (AMH) immunoassays are insufficiently sensitive to detect circulating AMH levels in ovulatory women approaching menopause. The aim of this study was to detect serum AMH levels across the menstrual cycle with age, using two new AMH enzyme-linked immunosorbent assay (ELISA) kits with increased sensitivity and differing specificity. MethodsSerum AMH levels were determined every 2 to 3 days across the interovulatory interval of menstrual cycles among women of early-mid reproductive age (18-35 y; n = 10) and late reproductive age (45-55 y; n = 17). Two highly sensitive AMH ELISAs (designated 24/32 and 24/37) with differing sensitivities were developed and applied to sera using a recombinant human pro-mature AMH preparation as reference. A third AMH ELISA (Gen II AMH ELISA kit; Beckman Coulter, Brea, CA) used was directed on mature-pro regions of AMH. ResultsAMH levels in all cycles were detectable with the 24/32 and 24/37 AMH ELISAs. AMH levels across the menstrual cycle were highly correlated (r = 0.98) between the 24/32 and 24/37 AMH ELISAs and the Gen II AMH ELISA (r = 0.94), but with large intracycle variations observed in older women. In late reproductive age, more than 95% of AMH values were detectable with the 24/32 and 24/37 AMH ELISAs, whereas only 36% of AMH values were detectable with the Gen II AMH ELISA. AMH levels were detected in cycles with lower antral follicle count and at a later age using the 24/32 and 24/37 AMH ELISAs compared with the Gen II AMH ELISA. AMH level correlated with antral follicle count in younger women, but not in older women. ConclusionsThe new 24/32 and 24/37 AMH ELISAs have the sensitivity to monitor ovarian follicle profiles in late reproductive age.

Digit ratios do not serve as anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome

BACKGROUND Polycystic ovary syndrome (PCOS) is heterogeneous in its clinical presentation and four major phenotypes have been identified. The precise etiology of PCOS is unknown; however, variable exposure to prenatal androgens may be responsible for the spectrum of endocrine and metabolic disturbances characteristic of this syndrome. Since prenatal testosterone exposure is known to decrease the ratio of the second to fourth finger lengths (2D:4D), we characterized the left and right hand 2D:4D in women with clinical variants of PCOS. We hypothesized that if prenatal androgens were involved in the development of the phenotypic spectrum of PCOS, then lower 2D:4D would be differentially expressed among clinical variants of the syndrome. METHODS Digit ratios were determined in 98 women diagnosed with PCOS by the 2003 international consensus guidelines and in 51 women with regular menstrual cycles, no clinical or biochemical signs of hyperandrogenism and normal ovarian morphology. Women with PCOS were categorized into four clinical phenotypes (i.e. Frank, Non-PCO, Ovulatory and Mild) and 2D:4D among groups were compared by Tukey-Kramer multiple comparisons tests. RESULTS Left (P = 0.77) and right (P = 0.68) hand 2D:4D were similar among the four clinical phenotypes and no phenotype of PCOS demonstrated a 2D:4D that differed from controls (Left Hand, P = 0.44 and Right Hand, P = 0.75). CONCLUSIONS Women with PCOS do not demonstrate finger length patterns that are consistent with increased prenatal androgen exposure. These findings do not preclude a role for prenatal androgens in the development of PCOS; however, low 2D:4D are not a characteristic of PCOS.

Assessment of ultrasonographic features of polycystic ovaries is associated with modest levels of inter-observer agreement

BackgroundThere is growing acceptance that polycystic ovaries are an important marker of polycystic ovary syndrome (PCOS) despite significant variability when making the ultrasound diagnosis. To better understand the nature of this variability, we proposed to evaluate the level of inter-observer agreement when identifying and quantifying individual ultrasonographic features of polycystic ovaries.MethodsDigital recordings of transvaginal ultrasound scans performed in thirty women with PCOS were assessed by four observers with training in Radiology or Reproductive Endocrinology. Observers evaluated the scans for: 1) number of follicles ≥ 2 mm per ovary, 2) largest follicle diameter, 3) ovarian volume, 4) follicle distribution pattern and 5) presence of a corpus luteum (CL). Lins concordance correlation coefficients and kappa statistics for multiple raters were used to assess inter-observer agreement.ResultsAgreement between observers ranged from 0.08 to 0.63 for follicle counts, 0.27 to 0.88 for largest follicle diameter, 0.63 to 0.86 for ovarian volume, 0.51 to 0.76 for follicle distribution pattern and 0.76 to 0.90 for presence of a CL. Overall, reproductive endocrinologists demonstrated better agreement when evaluating ultrasonographic features of polycystic ovaries compared to radiologists (0.71 versus 0.53; p = 0.04).ConclusionInter-observer agreement for assessing ultrasonographic features of polycystic ovaries was moderate to poor. These findings support the need for standardized training modules to characterize polycystic ovarian morphology on ultrasonography.

Improving inter-observer variability in the evaluation of ultrasonographic features of polycystic ovaries

BackgroundWe recently reported poor inter-observer agreement in identifying and quantifying individual ultrasonographic features of polycystic ovaries. Our objective was to determine the effect of a training workshop on reducing inter-observer variation in the ultrasonographic evaluation of polycystic ovaries.MethodsTransvaginal ultrasound recordings from thirty women with polycystic ovary syndrome (PCOS) were evaluated by three radiologists and three reproductive endocrinologists both before and after an ultrasound workshop. The following endpoints were assessed: 1) follicle number per ovary (FNPO), 2) follicle number per single cross-section (FNPS), 3) largest follicle diameter, 4) ovarian volume, 5) follicle distribution pattern and 6) presence of a corpus luteum (CL). Lins concordance correlation coefficients (rho) and kappa statistics for multiple raters (kappa) were used to assess level of inter-observer agreement (>0.80 good, 0.60 – 0.80 moderate/fair, <0.60 poor).ResultsFollowing the workshop, inter-observer agreement improved for the evaluation of FNPS (rho = 0.70, delta rho = +0.11), largest follicle diameter (rho = 0.77, delta rho = +0.10), ovarian volume (rho = 0.84, delta rho = +0.12), follicle distribution pattern (kappa = 0.80, delta kappa = +0.21) and presence of a CL (kappa = 0.87, delta kappa = +0.05). No improvement was evident for FNPO (rho = 0.54, delta rho = -0.01). Both radiologists and reproductive endocrinologists demonstrated improvement in scores (p < 0.001).ConclusionReliability in evaluating ultrasonographic features of polycystic ovaries can be significantly improved following participation in a training workshop. If ultrasonographic evidence of polycystic ovaries is to be used as an objective measure in the diagnosis of PCOS, then standardized training modules should be implemented to unify the approach to evaluating polycystic ovarian morphology.

Follicle number, not assessments of the ovarian stroma, represents the best ultrasonographic marker of polycystic ovary syndrome

OBJECTIVE To compare the diagnostic potential of ultrasonographic markers of ovarian morphology, used alone or in combination, to predict polycystic ovary syndrome (PCOS). DESIGN A diagnostic test study using cross-sectional data collected from 2006-2011. SETTING Academic hospital and clinical research unit. PATIENT(S) Eighty-two women with PCOS and 60 healthy female volunteers. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) Follicle number per ovary (FNPO), ovarian volume (OV), follicle number per single cross-section (FNPS), follicle distribution pattern, stromal area, ovarian area, stromal-to-ovarian area ratio (S:A), and stromal index (SI). RESULT(S) Follicle number per ovary best predicted PCOS (R(2) = 67%) with 85% sensitivity and 98% specificity, followed by OV (R(2) = 44%), and FNPS (R(2) = 36%). Neither S:A nor SI had predictive power for PCOS. In combination, FNPO+S:A and FNPO+SI most significantly predicted PCOS (R(2) = 74% vs. 73%, respectively). The diagnostic potentials of OV and FNPS were substantially improved when used in combination (OV+FNPO, R(2) = 55%). CONCLUSION(S) As a single metric, FNPO best predicted PCOS. Although the addition of S:A or SI improved the predictive power of FNPO, gains were marginal, suggesting limited use in clinical practice. When image quality precludes a reliable estimation of FNPO, measurements of OV+FNPS provide the next closest level of diagnostic potential.

Digit ratios by computer-assisted analysis confirm lack of anatomical evidence of prenatal androgen exposure in clinical phenotypes of polycystic ovary syndrome

BackgroundWe recently showed that women with four clinical phenotypes of polycystic ovary syndrome (PCOS) do not demonstrate anatomical evidence of elevated prenatal androgen exposure as judged by a lower ratio of the index (2D) to ring (4D) finger. However, those findings conflicted with a previous study where women with PCOS had lower right hand 2D:4D compared to healthy female controls. Both these studies used Vernier calipers to measure finger lengths - a method recently shown to be less reliable at obtaining finger length measurements than computer-assisted analysis.MethodsNinety-six women diagnosed with PCOS according to the 2003 Rotterdam criteria had their finger lengths measured with computer-assisted analysis. Participants were categorized into four recognized phenotypes of PCOS and their 2D:4D compared to healthy female controls (n = 48) and men (n = 50).ResultsDigit ratios assessed by computer-assisted analysis in women with PCOS did not differ from female controls, but were significantly lower in men. When subjects were stratified by PCOS phenotype, 2D:4D did not differ among phenotypes or when compared to female controls.ConclusionComputer-assisted measurements validated that digit ratios of women with PCOS do not show anatomical evidence of increased prenatal androgen exposure.

Age-related changes in major ovarian follicular wave dynamics during the human menstrual cycle.

ObjectiveChanges in antral follicle count, hormone production, and menstrual cyclicity as women age are well documented. However, age-related changes in ovarian follicular wave dynamics in women are not understood. The objective of this study was to test the hypothesis that major follicular wave dynamics (ie, those in which a dominant follicle develops) differ in women with age. MethodsA prospective, cross-sectional, observational study was conducted in 58 women of mid-reproductive age (MRA; 18-35 y; n = 27), late reproductive age (LRA; 36-44 y; n = 10), and advanced reproductive age (ARA; 45-55 y; n = 21). The number and diameters of all follicles ≥ 2 mm were quantified ultrasonographically every 2 to 3 days for one complete interovulatory interval (IOI). Only ovulatory cycles were evaluated. Antral follicle count and major follicular wave dynamics during the IOI were compared among age groups using SPSS version 19.0 (&agr; = 0.05). ResultsOne (36/58, 62%) or two (22/58, 38%) major follicular waves were observed during the IOI in all women evaluated. The prevalence of follicular-phase dominant follicles (FPDFs) and luteal-phase dominant follicles (LPDFs) was not different among the MRA, LRA, and ARA groups (FPDFs: 27/27 [100%], 10/10 [100%], and 20/21 [95%], respectively; LPDFs: 10/17 [37%], 3/10 [30%], and 10/21 [48%], respectively; P > 0.050). All FPDFs were ovulatory. One LPDF ovulated during menses in the ARA group; all other LPDFs in the MRA, LRA, and ARA groups were anovulatory. On average, LPDFs emerged earlier relative to ovulation (days −6, −2, and −2; P = 0.049), grew longer (11, 3, and 6 d; P = 0.005), and developed to a larger diameter (24, 11, and 11 mm; P = 0.032) in the ARA group versus the MRA and LRA groups. In follicular-phase major waves, there was a tendency for a greater prevalence of polyovulation as women aged (ARA 3/21 [14%] vs MRA 0/27 [0%]; P = 0.070). ConclusionsOne or two major follicular waves develop during the IOI, irrespective of age. The prevalence of LPDFs (range, 30%-50%) and FPDFs (range, 95%-100%) during the IOI does not differ with age. However, the growth dynamics of major waves change as women age. On average, LPDFs emerge earlier, grow for a longer period, and grow to a larger diameter in ovulatory women of advanced versus mid or late reproductive age. There is a greater tendency for polyovulation in the follicular-phase major wave as women age.

Women's Perceptions of Polycystic Ovary Syndrome Following Participation in a Clinical Research Study: Implications for Knowledge, Feelings, and Daily Health Practices

OBJECTIVE Polycystic ovary syndrome (PCOS) is a complex endocrine disorder that affects 6% to 10% of reproductive aged women. It is a poorly understood and often undiagnosed condition that has implications for the health of affected women. We assessed changes in knowledge, feelings, and daily health practices related to PCOS in clinical research study participants. METHODS Sixty-eight women who had received counselling and education about PCOS while participating in a clinical research study were invited to complete an online survey that assessed levels of concern, knowledge, healthy dieting, active living, and health care satisfaction before and after the study. Differences and associations between scores were analyzed by paired t tests and Pearson correlation. RESULTS Forty-three women (63%) completed the survey. After taking part in a clinical research study, participants believed they had increased knowledge of (P < 0.001) and concern about (P = 0.029) the etiology and health consequences of PCOS, better lifestyle practices (P < 0.001), and improved health care satisfaction (P = 0.045). Enhanced knowledge of PCOS was positively associated with changes in concern (P = 0.045), healthy dietary habits (P = 0.04), activity levels (P = 0.003), and health care satisfaction (P < 0.001). After the study, women felt empowered to participate in the management of their condition and communicate with their primary care providers. CONCLUSION Women with PCOS felt that they had more knowledge and motivation to implement preventive health strategies after participating in a clinical research study. Education about how PCOS affects their immediate and long-term health enabled women with PCOS to feel physical and psychological benefits and to engage more with their health care providers.