Abstract
Objective
To determine age-based criteria for polycystic ovary morphology.
Design
The study was a cross sectional, case-control design.
Setting
The study took place in an outpatient setting.
Subjects
Women with PCOS defined by hyperandrogenism and irregular menses (n=544) and controls with regular menses and no evidence of hyperandrogenism (n=666) participated. Parameters were tested in a second cohort of women with PCOS (n=105) and controls (n=32) meeting the same criteria.
Interventions
Subjects underwent a pelvic ultrasound documenting ovarian volume and maximum follicle number in a single plane.
Main Outcome Measures
A receiver operating characteristic curve was constructed to determine the ovarian volume and follicle number with the best sensitivity and specificity to define PCOS for age groups at approximately 5 year intervals from age 18 to >44 years.
Results
The best sensitivity and specificity were obtained using a threshold volume of 12 mL and 13 follicles age ≤24 yrs, 10 mL and 14 follicles age 25–29 yrs, 9 mL and 10 follicles age 30–34 yrs, 8 mL and 10 follicles age 35–39 yrs, 10 mL and 9 follicles for age 40–44 yrs and 6 mL and 7 follicles for age >44 years. Data from a second cohort confirmed the need to decrease volume and follicle number with increasing age to diagnose PCOS. Polycystic ovary morphology was most accurate at predicting the PCOS diagnosis for women aged 30 to 39 years.
Conclusion
The ovarian volume and follicle number threshold to define polycystic ovary morphology should be lowered starting at age 30 years.
Keywords: ultrasound, polycystic ovary syndrome, volume, follicle
Introduction
Polycystic ovary syndrome (PCOS) is a heterogenous disorder, originally identified by Stein and Leventhal in 1935, based on the abnormal anatomic ovarian morphology (1). Since the 1980s, ultrasonography has allowed for noninvasive assessment of polycystic ovarian morphology (PCOM)(2). In 2003, a group of PCOS investigators redefined the ultrasound criteria for polycystic ovary morphology at a consensus conference in Rotterdam (3). They determined that an ovarian volume greater than 10 mL provided excellent specificity for PCOS in a majority of studies, and used 12 or more follicles of 2 to 9 millimeters as the follicle number with the best sensitivity and specificity to distinguish polycystic ovary syndrome (4). However, with improvement in ultrasound technology it was recognized that the criteria defining polycystic ovary morphology needed to evolve to better distinguish the ovarian morphology in women with PCOS from that in women who do not have irregular menses and hyperandrogenism (5). A more recent review of the literature increased the follicle number threshold to ≥ 25 follicles to provide better specificity for PCOS, but found that the sensitivity of the measurement was compromised (5, 6).
None of the criteria take into account the normal decrease in ovarian volume and follicle number with age in women with PCOS and in women with regular menstrual cycles and no hyperandrogenism (7–9). We previously demonstrated that ovarian volume decreases log linearly and follicle number decreases linearly with age in women with PCOS and controls, studied both cross-sectionally and longitudinally (9). We have also demonstrated that virtually all women (97.3%) with PCOS diagnosed using the NIH criteria have PCO morphology on ultrasound and those that do not are older and have higher FSH levels (10). These findings support the need for age-based polycystic ovary morphology criteria. Therefore, the objective of the study was to determine the follicle number and ovarian volume with the best sensitivity and specificity to distinguish PCO morphology on ultrasound in reproductive age women within 5 year age groups.
Research Design and Methods
Subjects
All subjects were recruited as part of a genetics study with extensive phenotyping (10). PCOS subjects recruited at Massachusetts General Hospital in Boston, MA, from 2003 to 2013 were between the ages of 18 and 56 years (n=544). PCOS subjects recruited in Iceland from 2003 to 2006 were between the ages of 18 and 40 years (n=105). All subjects had oligomenorrhea (< 9 menstrual periods/yr) and clinical and/or biochemical evidence of hyperandrogenism, fulfilling the NIH criteria (11). Clinical hyperandrogenism was defined by: 1) an elevated Ferriman Gallwey score > 9 (12); or 2) acne on the face or back. Biochemical hyperandrogenism was defined as testosterone >63 ng/dL (2.8 nmol/L), DHEAS >430 µg/dL (1.16 µmoL/L) or androstenedione levels >3.8 ng/mL (13.3 nmol/L) (11).
Control subjects, aged 18 to 51 years, were recruited coincident with the PCOS subjects. Control subjects had regular menstrual cycles, 21 to 35 days, and no physical exam or biochemical evidence of hyperandrogenism in Boston (n=666) and Iceland (n=32). In Boston, all women were diagnosed with PCOS or confirmed as controls before the age of 40 years but some came back at a later age for a longitudinal study (9). They were only included in the data at their second visit, providing a broader age range for assessment.
Subjects were excluded for a personal history or biochemical evidence of late onset congenital adrenal hyperplasia (11). All subjects had normal thyroid function and prolactin levels and a follicular phase FSH level in the premenopausal range. Subjects were on no hormonal medication for at least 3 months, except for stable thyroid hormone replacement and were not taking metformin.
The study was approved by the Partners Human Research Committee and the Data Protection Commission of Iceland and the National Bioethics Committee of Iceland. All subjects provided written informed consent.
Women with PCOS were studied ≥10 days after their last menstrual period to avoid the time period in which LH is suppressed after a progesterone rise (13) and after a 12 hour fast (11). Control subjects were studied in the follicular phase. All subjects underwent a physical exam, blood draw for hormonal assessment and oral glucose tolerance test at baseline. Ultrasounds were performed by one operator in Boston (J.M. Adams), using the ATL HDI 1500 Ultrasound with a 4 to 8 mHZ convex array probe from 2003 to 2006. Ultrasounds were also performed by one operator in Iceland (trained by J.M. Adams) using the ATL Envisor Ultrasound with a 4 to 8 mHZ convex array probe, which was well matched to the Boston device, from 2003 to 2006. In April, 2006, the Boston group changed the ultrasound machine to a Phillips HD11 XE with a 4 to 8 mHZ endovaginal curved array transducer. In all cases, multiple images of the ovary were recorded. Ovarian volume was calculated using length × width × height in cm multiplied by 0.5233. All follicles were counted on a fixed image in a plane in which the maximum number of follicles was visualized. The maximum ovarian volume and maximum follicle number in the ovary with the maximum number of follicles was used for analysis, excluding the volume of an ovary with a dominant follicle (>10 mm) or a corpus luteum. Initial measurements were recorded in Boston and in Iceland and were over read by two observers (J.M.A, H.J.K, C.T.P. and/or C.K.W.). If readings were not in agreement, a consensus reading was agreed upon after review by all parties.
Using data from the Boston cohort, a receiver operating characteristic (ROC) curve was constructed for each (approximately) 5 year age group (18–24, >24–29, >29–34, >34–39, >39–44 and >44 years) for both ovarian volume and follicle number. Youden’s index (sensitivity + specificity − 1) was used to choose the value that maximized the sensitivity and specificity across all possible results, rather than optimize one or the other criteria to avoid bias. The sensitivity and specificity for ovarian volume and follicle number were then calculated in women with PCOS and controls from Iceland using the optimal cut point identified from the Boston cohort and levels surrounding that cut point to determine the maximum Youden’s index for each age interval with available data.
Results
The PCOS and control subjects exhibited the expected differences (Supplementary Tables 1–5). In the Boston subjects, there was no difference in the follicle number in women with PCOS from 2003–2006 (13.95±3.82) compared to 2006–2013 (13.71±3.98; p=0.5) or controls from 2003–2006 (9.20±3.21) compared to 2006–2013 (9.46±3.15; p=0.3) after the change in the ultrasound machine. There were slight differences in the ovarian volumes, with volume slightly larger from in women with PCOS from 2003–2006 (15.20±6.45 mL) compared to 2006–2013 (13.75±5.32 mL; p=0.01) and controls slightly smaller from 2003–2006 (8.58±3.99 mL) compared to 2006–2013 (9.35±3.95 mL; p=0.04). Thus, there were no systematic differences despite a change in the ultrasound machine.
The maximum average ovarian volume (14.7±6.8 vs. 9.3±4.1 mL; p=2×10−60) and follicle number (13.8±4.9 vs. 10.0±3.6; p=1×10−88) were greater in women with PCOS compared to controls from Boston overall and in the predesignated age groups (Figure 1). Evaluating the ROC curves in the designated age groups, there was no cutoff that resulted in both sensitivity and specificity of greater than 80% for either follicle number or ovarian volume (Table 1). Therefore, cutoffs providing the maximum sensitivity and specificity were determined using Youden’s Index (Table 1).
Figure 1.
Ovarian Volume and Follicle Number Cutoffs to Distinguish Polycystic Ovary Morphology from Normal Morphology. A) Ovarian volume and B) follicle number in women with PCOS (open gray circles) and controls (open black squares) as a function of age. Black horizontal lines indicate the chosen cutoff to distinguish polycystic ovary morphology from normal morphology.
Table 1.
Ovarian volume and follicle number cutoffs with resulting sensitivity and specificity. The bold results were chosen to maximize sensitivity and specificity for each age group according to the best Youden’s index.
| Age (yrs) |
PCOS/ Control Subject Number |
Ovarian Volume | Follicle Number | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Cutoff (mL) |
Sensitivity % (95% confidence limits) |
Specificity % (95% confidence limits) |
Youden’s Index |
Cutoff | Sensitivity % (95% confidence limits) |
Specificity % (95% confidence limits) |
Youden’s Index |
||
| ≤ 24 | 163/282 | 13 | 57 (49, 64) | 81 (76, 86) | 0.389 | 14 | 56 (48, 64) | 89 (85, 92) | 0.456 |
| 12 | 66 (58, 73) | 75 (69, 80) | 0.403 | 13 | 68 (60, 75) | 80 (75, 84) | 0.479 | ||
| 11 | 73 (65, 79) | 68 (62, 74) | 0.398 | 12 | 78 (71, 84) | 68 (62, 73) | 0.457 | ||
| 10 | 79 (71, 84) | 57 (51, 63) | 0.354 | 11 | 82 (75, 87) | 56 (50, 62) | 0.383 | ||
| >24–29 | 162/179 | 12 | 67 (59, 74) | 67 (59, 74) | 0.344 | 14 | 57 (50, 65) | 92 (86, 95) | 0.489 |
| 11 | 75 (68, 82) | 61 (53, 68) | 0.364 | 13 | 68 (61, 75) | 80 (73, 85) | 0.484 | ||
| 10 | 85 (78, 90) | 54 (46, 62) | 0.380 | 12 | 84 (77, 89) | 64 (57, 71) | 0.480 | ||
| >29–34 | 114/96 | 12 | 66 (56, 74) | 81 (71, 88) | 0.476 | 12 | 75 (67, 83) | 79 (70, 86) | 0.544 |
| 11 | 79 (70, 85) | 74 (66, 85) | 0.523 | 11 | 81 (73, 87) | 73 (63, 81) | 0.535 | ||
| 10 | 82 (73, 88) | 70 (59, 79) | 0.524 | 10 | 94 (87, 97) | 68 (59, 77) | 0.621 | ||
| 9 | 90 (83, 95) | 65 (54, 75) | 0.532 | 9 | 98 (94, 99) | 59 (49, 68) | 0.572 | ||
| >34–39 | 70/66 | 10 | 74 (62, 83) | 80 (66, 89) | 0.512 | 11 | 76 (64, 84) | 88 (77, 94) | 0.633 |
| 9 | 76 (64, 85) | 73 (60, 84) | 0.508 | 10 | 88 (78, 94) | 78 (67, 86) | 0.660 | ||
| 8 | 87 (77, 93) | 65 (51, 77) | 0.528 | 9 | 94 (85, 98) | 66 (53, 76) | 0.595 | ||
| >39–44 | 28/22 | 10 | 68 (47, 84) | 88 (69, 96) | 0.532 | 10 | 68 (49, 82) | 82 (66, 91) | 0.497 |
| 9 | 73 (52, 87) | 83 (64, 93) | 0.519 | 9 | 75 (57, 87) | 76 (59, 87) | 0.508 | ||
| 8 | 77 (57, 90) | 63 (43, 79) | 0.460 | 8 | 82 (64, 92) | 58 (41, 73) | 0.397 | ||
| >44 | 7/10 | 7 | 57 (25, 84) | 67 (35, 88) | 0.238 | 9 | 71 (36, 92) | 80 (49, 94) | 0.514 |
| 6 | 86 (45, 97) | 67 (35, 88) | 0.452 | 7 | 100 (65, 100) | 60 (31, 83) | 0.600 | ||
For the best compromise between sensitivity and specificity a threshold volume of 12 mL for women ≤24 yrs, 10 mL for age 25 to 29 yrs, 9 mL for ages 30 to 34 yrs, 8 mL for ages 35 to 39 yrs, 10 mL for ages 40 to 44 yrs, and 6 mL for over age 44 yrs were chosen (Table 1 and Figure 1). For ages 30 to 34, 35 to 39 and 40 to 44 yrs, the accuracy of the PCOS diagnosis was the best (Area Under the Curve [AUC] 0.85, 0.86 and 0.83, respectively) (Figure 2), whereas for the younger ages, ≤24 and 25 to 29 yrs, the same sensitivity resulted in lower specificity (AUC 0.77 and 0.75). When ages >44 yrs were examined, there was less data so the accuracy was not as robust (AUC 0.76).
Figure 2.
Receiver Operating Characteristic (ROC) Curves for Ovarian Volume and Follicle Number. ROC curves demonstrating the sensitivity and specificity of A) ovarian volume and B) follicle number as a single factor to distinguish polycystic ovary syndrome subjects from controls for age groups 18–24 (gray circles), 25–29 (open circles), 30–34 (closed triangles), 35–39 (solid line) and 40–44 yrs (X).
For the best compromise between sensitivity and specificity a threshold follicle number of 10 for ages 30 to 39 yrs was chosen (Table 1 and Figure 1). For ages 40 to 44 yrs a threshold of 9 follicles was chosen and over 44 years a threshold of 7 was chosen. For women younger than age 24 yrs, the best threshold for follicle number was 13, but the best threshold for ages 25 to 29 was 14. As with ovarian volume, follicle number at age 30 to 34 and 35 to 39 yrs had the best accuracy for predicting PCOS (AUC 0.87 and 0.92) when compared to ages 18 to 24 and 25 to 29 yrs (AUC 0.80 and 0.83) (Figure 2). It was easier to choose a value that represented a good compromise between sensitivity and specificity for women at the older ages. There was less data for ages 40 to 44 and over 44 yrs, so the accuracy was not as robust (AUC 0.81 and 0.80).
The sensitivity and specificity of the chosen cutoffs for ovarian volume and follicle number were examined in an independent set of data. The sensitivity of the chosen parameters for ovarian volume ranged from 50% in the youngest group to 88% (Table 2). However, changing the ovarian volume by 1 mL improved the sensitivity and specificity in the 30 to 39 year old age group. The sensitivity of the chosen parameters for follicle number ranged from 14% to 84%. If the follicle number was changed by 1–2 units in the groups under age 35, the sensitivity or specificity was improved (Table 2).
Table 2.
Sensitivity and specificity of ovarian volume and follicle number cutoffs with resulting sensitivity and specificity in an additional cohort. The bold results were chosen to maximize sensitivity and specificity for each age group according to the best Youden’s index.
| Age (yrs) |
Ovarian volume (mL) / Follicle Number |
Ovarian Volume | Follicle Number | ||||
|---|---|---|---|---|---|---|---|
| Sensitivity % |
Specificity % |
Youden’s Index |
Sensitivity % |
Specificity % |
Youden’s Index |
||
| ≤24 | 12/13 | 50 | NA | NA | 50 | NA1 | NA |
| 10/12 | 80 | NA | NA | 80 | NA | NA | |
| >24–29 | 10/14 | 53 | NA | NA | 14 | NA | NA |
| 9/12 | 68 | NA | NA | 62 | NA | NA | |
| >29–34 | 10/11 | 88 | 80 | 0.68 | 84 | 100 | 0.84 |
| 9/10 | 88 | 40 | 0.28 | 84 | 71 | 0.55 | |
| >34–39 | 8/10 | 80 | 91 | 0.71 | 66 | 84 | 0.50 |
| 9/9 | 77 | 100 | 0.77 | 66 | 74 | 0.40 | |
NA-not available. There was an insufficient number of controls to calculate specificity in the given age groups.
Discussion
The data suggest that the parameters used to document polycystic ovary morphology, both ovarian volume and follicle number, should decrease with increasing age. The specific cutoffs identified had good specificity and sensitivity between ages 30 and 40 years, whereas the ovarian volume and follicle number measurements were less able to distinguish PCOS in women under the age of 30 years and data were limited over age 40 years. When examined in a second population, the sensitivity of the chosen parameters was poor under age 30 years, but was able to distinguish PCOS at older ages. Thus, age specific ultrasound parameters for polycystic ovary morphology would improve the distinction of PCOS over age 30 yrs, a time when other Rotterdam diagnostic criteria become more difficult to apply based on improvement in menstrual cycle frequency and the fall in androgen levels (14).
Recent data have expanded the follicle number required to document polycystic ovary morphology in young women to improve specificity (5). In the recent update, ≥25 follicles in the whole ovary and ovarian volume ≥10 mL were chosen to define polycystic ovary morphology in women ages 18 to 35 years, with no additional consideration for age. The age-related decline in female reproductive function due to the reduction of the ovarian follicle pool has been well established in control women (7, 8). A parallel decline also occurs in the follicle count in a single plane in women with PCOS, although the decline starts from a higher baseline (9). There is a small decrease in ovarian volume across age in control women (15, 16). However, ovarian volume is greater in women with PCOS and exhibits a greater rate of decline with age, resulting in matching ovarian volume after menopause (9). Thus, the defining parameters for polycystic ovary morphology need to be considered in the context of age to optimize both sensitivity and specificity for ovarian volume and follicle number in women with PCOS.
Overall, the optimal ovarian volume and follicle number threshold did decrease with age in the current large data set. In women under age 30 yrs, follicle numbers of 12–14 had very similar Youden’s indices and the particular cutoff choices were quite close. There was an increase rather than a decrease in the cutoff ovarian volume in the 40 to 44 year old age group, likely based on the small number of data points, which decreased power. Thus, examining the ovaries of additional women with PCOS over age 40 yrs would help optimize the cutoffs.
Recent studies using ROC curves to determine the cutoff for the best sensitivity and specificity to define PCOS have pooled women aged 18 to 35 years. These studies demonstrate ROC curves with areas greater than 0.94 for follicle number and 0.88 for ovarian volume (17, 18), similar to the area under the curve for ages 30 to 39 years in the current data. Of note, when examining follicle number in a single plane, a measurement analogous to that in the current study, a threshold of 9 resulted in a 69% sensitivity and 90% specificity, which is a much lower number of follicles than our own data would indicate if data from age 18 to 35 yrs had been analyzed together (17). The plane with the maximum number of follicles was used for assessment in the current study, but the choice of plane was not specified in previous studies and measurements from two ovaries were averaged (17), perhaps accounting for the differences. Using a second set of ultrasounds performed independently but over read by the investigators, the thresholds for ovarian volume and follicle number also provided good sensitivity and specificity, within a range of 1 mL for ovarian volume and 1 follicle in a single plane. Thus, the data appears to be robust and will be tested in additional cohorts.
While it has been suggested that follicle number per ovary provides a more accurate assessment of polycystic ovary morphology (17, 19), the data are not as simple to obtain in large studies. Some studies do not find a greater discrimination using follicle number per ovary compared to follicle number in a single plane (20). Others demonstrate a similar AUC when comparing follicle number per ovary to a combination of follicle number in a single plane and the universally measured ovarian volume (19). In the context of our very large study, which started when follicle number in a single plane was the recommended measure to document polycystic ovary morphology, the simplicity and discriminatory power are sufficient to recommend the current measurements to define polycystic ovary morphology. The data were not available to examine total follicle number as a function of age, but could be assessed in future studies.
Although AMH levels have been considered equal or superior to antral follicle counts in distinguishing PCOS from control subjects, levels are not yet considered sufficiently accurate for diagnostic purposes based on assay limitations (5). AMH levels were not available in the current data for women with PCOS. Additional studies are needed to determine whether the available AMH assays also need age-based cutoffs for diagnostic purposes in PCOS.
Conclusions
The ovarian volume and follicle number threshold used to define polycystic ovary morphology should be lowered starting at age 30 years. The accuracy of the ovarian volume and follicle number to diagnose PCOS improves after age 30 years.
Supplementary Material
Acknowledgments
The project described was supported by Award Number R01HD065029 from the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, Award Number 1 UL1 RR025758, Harvard Clinical and Translational Science Center, from the National Center for Research Resources and award 1-10-CT-57 from the American Diabetes Association. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute Of Child Health & Human Development, National Center For Research Resources, the National Institutes of Health or the American Diabetes Association.
C.K.W. has received consulting fees from Novartis and royalties from UptoDate unrelated to the current topic.
Footnotes
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