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Departments of Obstetrics and Gynecology (R.S.L., P.C., W.C.D.) and Health Evaluation Sciences (A.R.K., C.M.B.), Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and Division of Endocrinology, Metabolism, and Molecular Medicine (A.D.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611-3008
Address all correspondence and requests for reprints to: Richard S. Legro, M.D., Department of Ob/Gyn, P.O. Box 850, 500 University Drive, M. S. Hershey Medical Center, Hershey Pennsylvania 17033. E-mail: rsl1{at}psu.edu.
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Abstract |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Indeed, a recent jointly sponsored American Society of Reproductive Medicine/European Society of Human Reproduction and Endocrinology consensus conference on diagnostic criteria and sequelae of PCOS included the polycystic ovary as one of the key features of the syndrome (10, 11). A subsequent publication defined a polycystic ovary on both morphometric and volume criteria (12). However, the diagnostic criteria for PCOS, in the absence of evidence-based criteria, such as the predictive value for current or long-term pathology, rest primarily on expert opinion. Ultimately such criteria should be substantiated by data in the same way, for example, that the cutoff in blood glucose values for diagnosing diabetes is based on ongoing scientific scrutiny of existing data (13).
Whereas many of the women with polycystic ovaries have stigmata of the syndrome, including hyperandrogenism, chronic anovulation, and insulin resistance, some affected women appear to be endocrinologically normal (14). However, this latter group of women often have subtle reproductive endocrine abnormalities that may become apparent only after provocative testing (15). Furthermore, it has been proposed that in women in whom the syndrome is diagnosed based on endocrine criteria (unexplained hyperandrogenic chronic anovulation), the presence of polycystic ovaries is a marker for insulin resistance (16). Moreover, in women with oligomenorrhea, a positive correlation between ovarian volume and insulin sensitivity has been reported (17).
In contrast, other studies have not found an association between polycystic ovaries and cardiovascular risk factors, such as circulating insulin and lipid levels in women with PCOS (18). Thus, there are conflicting data about the significance of polycystic ovary morphology in women with the endocrine syndrome of PCOS. We performed this study to determine whether there was an association between the morphology or size of the ovaries and parameters of insulin sensitivity or reproductive hormone levels in women with PCOS.
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Patients and Methods |
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We studied 88 unrelated women with PCOS and 21 control women aged 17–45 yr. All studies were approved by the Institutional Review Board of the Pennsylvania State University College of Medicine (Penn State), and all subjects gave written informed consent before study. All women were in good health, euthyroid, and, for at least 1 month before each study, were not taking any medication (except for oral contraceptive agents, which were stopped for 3 months before study) known to affect sex hormone or carbohydrate metabolism. The diagnosis of PCOS was made by the presence of chronic anovulation as defined by six or fewer menses per year in association with elevated circulating androgen levels (19). Nonclassical 21-hydroxylase deficiency, hyperprolactinemia, and androgen-secreting tumors were excluded by appropriate tests before the diagnosis of PCOS was made (5, 20).
Twenty-one reproductively normal, control women with 27- to 35-d menstrual cycles were studied as a reference population. These women did not have a history of hypertension or diabetes mellitus, personally or in a first-degree relative. All control women were examined by one of the study investigators and had no hirsutism (Ferriman-Gallwey score < 8) (21). Control women had normal glucose tolerance based on a 75-g 2-h oral glucose tolerance test applying World Health Organization (WHO) criteria (22).
Study protocol
All studies were performed between 0800 and 1100 h after a 3-d 300-g carbohydrate diet and an overnight fast of 10–12 h. Studies were performed in PCOS women without regard to the last episode of vaginal bleeding, and all subjects were anovulatory or in the follicular phase at the visit with a serum progesterone level less than 3 ng/ml. No woman had diagnosed diabetes mellitus before study. Height and weight were obtained on all subjects and body mass index (BMI) was calculated by dividing weight by height squared (kilograms per square meter). An iv catheter was inserted, the vein was kept open with an infusion of 0.9% normal saline at 30 cc/h, an oral glucose tolerance test (OGTT) was performed, and blood was sampled through the catheter.
All subjects underwent a 75-g oral glucose load and blood was obtained for glucose determinations at 0, 30, 60, 90, and 120 min. Additional blood was obtained at time 0 for analysis of testosterone (T), non-SHBG-bound T (uT), dehydroepiandrosterone sulfate (DHEAS), and gonadotropins. Glucose tolerance was assessed by the WHO criteria (22). Normal glucose tolerance is defined as a 2-h glucose stimulated value less than 140 mg/dl (7.71 mmol/liter), impaired glucose tolerance is defined as a 2-h value from 140 to 199 mg/dl (7.71–10.96 mmol/liter), and type 2 diabetes mellitus is defined as a 2-h value of 200 mg/dl or greater (
11.02 mmol/liter). We used the insulin sensitivity index (ISI0,120) based on the fasting (0 min) and 120-min OGTT insulin and glucose concentrations as developed by Gutt et al. (23). The ISI0,120 has been highly correlated with the rate of whole-body glucose disposal during the euglycemic insulin clamp as originally developed by DeFronzo et al. (24).
Upon completion of the OGTT, a transvaginal ultrasound was performed of the pelvis. The following measures were obtained: endometrial thickness, ovarian size in three dimensions, the size of the largest ovarian follicle, and ovarian morphology. Polycystic ovary morphology (PCOM or non-PCOM) was determined by the criteria of Adams et al. (25), which includes the presence of 10 or more peripheral follicular cysts 8 mm or less in diameter in one plane along with increased central ovarian stroma. We did not use the criteria of Balen et al. (12) of 12 or more follicles because we commenced this study before the publication of these guidelines. No subject studied had a developing follicle (defined as largest follicle with mean diameter > 10 mm) or an ovarian cyst.
Ovarian size was obtained by measuring the largest plane of the ovary in two dimensions and then turning the vaginal probe 90 degrees and obtaining a third measurement. Volume of the ovary was calculated using the formula for an ellipsoid [length x height x width x (
/6)] (26). In all subjects both ovaries were visualized on ultrasound, allowing for the calculation of total ovarian volume (right + left ovarian volume). Polycystic ovary volume (PCOV or non-PCOV) was determined by the criteria of Balen et al. (12), which is defined as at least one ovary having a volume greater than 10 cm3 with no cysts or follicles greater than 10 mm mean diameter. Endometrial thickness was determined as the largest anterior-posterior measurement of the endometrium in the sagittal plane.
Assays
Assays for total T, DHEAS, and gonadotropins were performed using Diagnostic Products Corp. (Los Angeles, CA) Coat-A-Count kits (19). Free and weakly bound T was measured using a modification of the procedure of Tremblay and Dube (27). Plasma glucose levels were determined by the glucose oxidase technique (28). Insulin was determined with a double-antibody method using reagents obtained from Linco Research, Inc. (St. Charles, MO) (29). All assays had intra- and interassay coefficients of variation less than 10%.
Data analysis
For continuous variables, comparisons between groups (PCOM vs. non-PCOM, PCOV vs. non-PCOV, and PCOS vs. control) were assessed using analysis of covariance (ANCOVA) models adjusting for the effects of age and BMI. Logarithmic transformations of the continuous variables were taken to meet ANCOVA modeling assumptions. The data are reported as the model-based mean estimate, adjusted for age and BMI and the 95% confidence interval (CI). The association between total ovarian volume and reproductive and metabolic parameters was assessed after adjusting for age and BMI using the Spearman partial correlation coefficient within PCOS and control women separately. All analyses were performed using either SAS statistical software (SAS Institute Inc., Cary, NC) or S-Plus software (Insightful Corp., Seattle, WA).
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Results |
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. BMI, 2-h postchallenge glucose, and insulin levels as well as integrated OGTT glucose and insulin responses were significantly higher in PCOS than the control women. The ISI0,120 was significantly higher in control women than women with PCOS (Fig. 1). By design, all of the control women had normal glucose tolerance. Based on WHO criteria applied to 2-h postchallenge glucose levels, 25 women with PCOS and PCOM had impaired glucose tolerance and four women had type 2 diabetes mellitus, compared with five and two women, respectively, with normal ovaries. PCOS women had a higher total ovarian volume than the control women. For all hormonal parameters (sex steroids and gonadotropins), with the exception of FSH, PCOS women had significantly higher levels than the control women.
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We compared reproductive and metabolic parameters between women with PCOS plus PCOM with women with PCOS minus PCOM (Table 2). Women with PCOS plus PCOM had lower FSH levels than women with PCOS minus PCOM. However, there were no differences in the ISI0,120, fasting or 2-h postchallenge glucose or insulin values or integrated OGTT glucose and insulin responses. Furthermore, there were no differences in circulating androgen or gonadotropin levels between these groups. We did not perform these analyses within the control women given the low prevalence of PCOM (n = 2).
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). Women with PCOS plus PCOV had a higher LH to FSH ratio than women with PCOS minus PCOV. Control women with PCOV had a greater endometrial thickness than control women without PCOV. There were no differences in the ISI0,120, fasting or 2-h postchallenge glucose or insulin values or integrated OGTT glucose and insulin responses or circulating androgen or gonadotropin levels between PCOV and non-PCOV within the women with PCOS and the control women.
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). There were no significant correlations between total ovarian volume and any parameter of glucose metabolism or reproductive hormone levels, with the exception of FSH, in either the women with PCOS or the control women. In women with PCOS, total ovarian volume was modestly correlated with FSH (R = –0.25; P = 0.02). Furthermore, there were no differences in the correlations between the groups (PCOS vs. control) for total ovarian volume and any parameter of glucose metabolism (including ISI0,120 in Fig. 2) or reproductive hormone levels (including T in Fig. 3), with the exception of the LH to FSH ratio (P = 0.02) (Table 3
).
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Discussion |
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Our findings of no association between polycystic ovaries and insulin resistance varies from prior studies, which found a positive association between either polycystic ovaries (16) or ovarian volume with insulin resistance (17). The former study is limited by the small sample size (only five with polycystic ovaries). The latter study by Pache et al. (17) found only a modest correlation between ovarian volume and insulin resistance (R = 0.23, P < 0.05). Furthermore, they used only fasting measures of glucose and insulin to calculate insulin resistance. Our study used an ISI from a dynamic test using the fasting (0 min) and 120-min glucose and insulin concentrations. Whereas it is an oversimplification to label an OGTT as a measure of insulin sensitivity, multiple studies have validated strong correlations between such indices derived from the OGTT with the reference method of euglycemic clamps (23, 31, 32, 33). We did note a borderline significant negative correlation between ovarian volume and fasting glucose levels, suggesting that a larger sample size may have yielded slightly different results.
We found modest associations between gonadotropins and ovarian ultrasound parameters. Among women with PCOS, those with PCOM had lower FSH levels, compared with those without this morphology, and those with PCOV had a higher LH to FSH ratio. These findings are consistent with a population-based study that found a significant correlation between ovarian volume and LH (positive) and FSH (negative) (34). Early-follicular-phase elevations in FSH have also been associated with aging and diminished ovarian reserve in response to ovulation induction (35). A similar mechanism may be operating here in PCOS women. Women with PCOS plus PCOM also tended to be younger. Thus, the most likely explanation for an elevation in basal FSH levels within the PCOS/PCOM group is ovarian aging (34).
Other reproductive features of PCOS, including elevated circulating androgen levels and menstrual irregularity have been found to normalize with age, especially as women enter their fifth decade of life (36, 37). Little has been published about the changes in polycystic ovary morphology with age, but there are reports suggesting this abnormality resolves with age. For example, follow-up ovarian ultrasound examinations have shown that there are fewer ovarian follicles in older women with PCOS whose cycle have become regular, implying a resolution of the PCO morphology (38, 39). Similarly, large cross-sectional studies show fewer ovarian follicles with age in women with PCOS (40). Unfortunately, there are few natural history studies of changes in ovarian morphology with age, in either women with PCOS or the general population (41).
Some authors have suggested that 12 or more follicles 2–9 mm in size per ovary is a critical threshold for identifying women with metabolic abnormalities (42). This was further promulgated in the recently published international consensus criteria for the ultrasound diagnosis of the polycystic ovary (12). However, because we began this study before the publication of these guidelines and we did not perform follicles counts above 10, we cannot perform such an analysis retrospectively based on a cutoff of 12 follicles 2–9 mm as opposed to 10 follicles 2–8 mm (25). As part of our study design and consistent with the recommendations of these guidelines, we did not include in the study subjects with follicles greater than 10 mm in diameter due to their confounding effects on ovarian volume, compared with women with PCOS without known cyclic changes in the follicle size or ovarian volume.
Another criterion in additional to follicle size and count proposed in the guidelines was a single ovarian volume greater than 10 cm3 (with no follicle/cyst > 10 mm mean diameter) (12). Our PCOS group had a combined (right + left) ovarian volume (and 95% CI) greater than 20 cm3, consistent with this cutoff. Similarly, our controls had a combined ovarian volume (as well as the 95% CI) less than 20 cm3, consistent with these guidelines. Nonetheless, at least one PCOV was present in close to half of control women. The mean ovarian volume in a large population-based U.S. study was 6.6 cm3 in women younger than 30 yr (43). Our average mean ovarian volume was 8.0 cm3, and this slight increase in our controls may be due to our selection criteria: young, healthy, and off confounding (and suppressive) medications (34, 41). Use of hormones has been associated with smaller ovarian volumes (43). Furthermore, population-based studies of this cutoff for the PCOV are recommended because our control sample size is too small and too select to generalize to the larger population.
Our study has several limitations. Our women with PCOS were more obese than those found in other countries, but our mean BMI of 36 is representative of other large U.S. multicenter clinical trials of women with PCOS (44). Whereas obesity is a significant confounder in visualizing ovaries transabdominally (45), there is less literature to support that this is a confounder with transvaginal scans; nonetheless, it merits mention. We may have found a stronger correlation between ultrasound features of the ovary and other circulating androgens. We chose to assay T because it is still the largest contributor in terms of bioactivity to the circulating androgen pool and also because it has been used in several important clinical trials to identify women with PCOS (44, 46). Another androgen of lower bioactivity but with a greater ovarian contribution, such as androstenedione, may have had more association with the polycystic ovary morphology or volume. Our failure to detect an association between ovarian volume and T levels, which approached borderline significance, may also have been a result of our limited sample size.
We also did not perform quantitative follicle counts on each ovary that may have correlated better with the parameters studied. We also did not apply more sophisticated analyses of our ultrasound data (47, 48) or other ultrasound technologies, such as Doppler flow studies or three-dimensional ultrasonography, to further qualify and quantify polycystic ovary morphology (49, 50). These methodologies are still primarily of research interest and have not received widespread clinical application (51). We also did not assess inter- and intraobserver variation for either polycystic ovaries or ovarian volume. Previous studies have shown very low intra- and interobserver variation for the measurement of ovarian volume by ultrasound (52, 53), and this parameter has been used in a number of settings in women’s health in addition to identifying polycystic ovaries (54). The observer variation for the assessment of polycystic ovaries is a more subjective measure (55) and may be higher (56). This suggests the need for evidence-based guidelines for the recognition of polycystic ovaries.
In our population of control women, who were carefully screened to exclude those with hirsutism, hyperandrogenemia, and glucose intolerance, polycystic ovaries were an infrequent finding (<10%). This observation suggests that earlier prevalence studies of polycystic ovary morphology (14, 57, 58) included women with unrecognized reproductive or metabolic abnormalities, consistent with the observation that many women with polycystic ovary morphology have evidence, however subtle, of androgen excess and/or insulin resistance with more detailed testing (59, 60, 61). The low prevalence of polycystic ovary morphology in our reproductively and metabolically normal women supports the hypothesis that polycystic ovaries are intrinsically abnormal and may be the ovarian morphologic consequence of intrinsic defects in follicular development and steroidogenesis (62). Furthermore, our conclusions about the meaning of ovarian volume and morphology within PCOS should not be extrapolated to the larger population in whom studies have detected significant associations with reproductive and metabolic abnormalities (63).
In conclusion, polycystic ovaries cluster in a group of women with marked reproductive and metabolic abnormalities, and their presence in the greater female population should trigger suspicion of PCOS. However, the role of ultrasonography in the diagnosis and management of women who present with hyperandrogenic chronic anovulation [or PCOS based on two of three of the recent consensus diagnostic criteria (10, 11)] is uncertain. There are still indications to perform ultrasonography of the pelvis in women who present with these endocrine criteria for PCOS, i.e. to screen for anatomic abnormalities, such as polyps or endometrial hyperplasia causing dysfunctional uterine bleeding (64), or identify predictive factors for success or complications of ovulation induction (30, 65). However, neither the morphology nor volume of the ovaries identify distinctive metabolic or reproductive abnormalities in women with hyperandrogenic chronic anovulation and routine ovarian ultrasonography in this group may be unnecessary. We look forward to further prospective and population-based studies exploring these issues.
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Footnotes |
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First Published Online February 15, 2005
Abbreviations: ANCOVA, Analysis of covariance; BMI, body mass index; CI, confidence interval; DHEAS, dehydroepiandrosterone sulfate; ISI, insulin sensitivity index; OGTT, oral glucose tolerance test; PCOM, polycystic ovary morphology; PCOS, polycystic ovary syndrome; PCOV, polycystic ovary volume; T, testosterone; uT, non-SHBG-bound testosterone.
Received February 9, 2004.
Accepted February 3, 2005.
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