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The Journal of Clinical Endocrinology & Metabolism 90(5):25712579

Copyright 2005 by The Endocrine Society
doi: 10.1210/jc.2004-0219

Polycystic Ovaries Are Common in Women with

Hyperandrogenic Chronic Anovulation but Do Not
Predict Metabolic or Reproductive Phenotype
Richard S. Legro, Percy Chiu, Allen R. Kunselman, Christina M. Bentley, William C. Dodson, and
Andrea Dunaif
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
Polycystic ovary syndrome (PCOS) is a heterogeneous disorder of unexplained hyperandrogenic chronic anovulation. Experts have recommended including the morphology and volume of the ovary in the diagnostic criteria for PCOS. We
performed this study to determine whether there was an association between the morphology and size of the ovaries and
markers of insulin sensitivity as determined by dynamic testing within women with PCOS or compared with a group of
control women. We then examined reproductive parameters.
We studied 88 unrelated PCOS women and 21 control women,
aged 17 45 yr. All were in the early follicular phase or its
equivalent (no follicle with > 10 mm diameter and anovulatory serum progesterone level < 3 ng/ml). Subjects underwent
on the same day a phlebotomy for baseline hormones, a 2-h
oral glucose tolerance test, and transvaginal ultrasound to
determine the morphology and volume of the ovaries. Ninetyfive percent (84 of 88) of women with PCOS and 48% (10 of 21)
of the control women had polycystic ovaries using the criteria
of at least one ovary greater than 10 cm3 (PCOV) and/or polycystic ovary morphology (PCOM) using the criteria of 10 or

OLYCYSTIC OVARY SYNDROME (PCOS) was first diagnosed by the presence of enlarged ovaries by pelvic
exam combined with a history of amenorrhea and hirsutism
(1). A characteristic abnormal morphology was subsequently
confirmed by examining histologic sections of the ovary (1).
The syndrome was considered to have only reproductive
consequences (2) until the discovery that insulin resistance
was frequently found in women with PCOS (3, 4). This finding led to the recognition that PCOS was a multisystem
endocrinopathy characterized by hyperandrogenism and
chronic anovulation (57). Nevertheless, debate continues
about the significance of polycystic ovary morphology, in
both apparently normal women and women with the endocrinopathy of PCOS (8, 9).
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.
JCEM is published monthly by The Endocrine Society (http://www.
endo-society.org), the foremost professional society serving the endocrine community.

more peripheral follicular cysts 8 mm in diameter or less in

one plane along with increased central ovarian stroma. PCOM
was a better discriminator than PCOV between PCOS and
control women. The odds of women with PCOS having PCOM
were elevated 50-fold compared with controls (odds ratio, 50;
95% confidence interval, 10 240; P < 0.0001), whereas the odds
of PCOV were elevated 5-fold in women with PCOS (odds ratio,
4.6; 95% confidence interval, 1.712.6; P 0.003). Neither the
insulin sensitivity index, fasting or 2-h values, or any integrated measures of glucose and insulin varied in women according to either morphology or volume, nor was there an
association with circulating androgen levels. Women with
PCOS and PCOM had lower FSH levels than women with
PCOS and non-PCOM. Women with PCOS and PCOV had a
higher LH to FSH ratio than women without PCOV and PCOS.
These data support the hypothesis that polycystic ovaries are
an abnormal finding. However, neither the morphology nor
the volume of the ovaries is associated with distinctive metabolic or reproductive phenotypes in women with PCOS.
(J Clin Endocrinol Metab 90: 25712579, 2005)

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

2571

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J Clin Endocrinol Metab, May 2005, 90(5):25712579

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.
Patients and Methods
Patients
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-SHBGbound 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 (7.7110.96 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 per-

Legro et al. PCO Morphology in PCOS

formed 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 height width (/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).

Results

Baseline characteristics of the two groups are found in

Table 1. 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.
Ninety-five percent of women (84 of 88) with PCOS and
48% control women (10 of 21) had polycystic ovaries using

Legro et al. PCO Morphology in PCOS

J Clin Endocrinol Metab, May 2005, 90(5):25712579

2573

TABLE 1. Model-based estimates adjusting for age and BMI for indices of glucose metabolism, reproductive hormones, and other
ultrasound parameters according to diagnosis (PCOS/control)
Variable

Age (yr)b
BMI (kg/m2)b
OGTT parameters
Fasting glucose (mg/dl)
Fasting insulin (U/ml)
Fasting glucose to insulin ratio
Glucose 2 h (mg/dl)
Insulin 2 h (U/ml)
Integrated glucosec
Integrated insulinc
ISI0,120 from OGTT
Hormonal parameters
DHEAS (ng/ml)
T (ng/dl)
uT (ng/dl)
LH to FSH ratio
FSH (mIU/ml)
Ultrasound parameters
Total ovarian volume (right left
ovarian volume) (cm3)
Endometrial thickness (mm)

PCOS (n 88)
[mean (95% CI)]

Control (n 21)
[mean (95% CI)]

Ratio of PCOS to
control (95% CI)

P valuea

27.7 (26.4, 29.0)

35.1 (33.5, 36.9)

29.5 (26.8, 32.4)

25.8 (23.4, 28.5)

0.9 (0.8, 1.0)

1.4 (1.2, 1.5)

0.24
<0.001

92 (89, 94)
21 (19, 23)
4.4 (4.0, 4.8)
130 (123, 138)
109 (93, 128)
16747 (16024, 17502)
12699 (11306, 14263)
50 (46, 54)

86 (81, 91)
18 (15, 22)
4.8 (3.9, 5.8)
92 (82, 104)
43 (30, 60)
12700 (11238, 14353)
8327 (6034, 11491)
82 (69, 98)

1.1 (1.0, 1.1)

1.2 (0.9, 1.5)
0.9 (0.7, 1.1)
1.4 (1.2, 1.6)
2.6 (1.7, 3.8)
1.3 (1.2, 1.5)
1.5 (1.1, 2.2)
0.6 (0.5, 0.7)

0.05
0.18
0.43
<0.001
<0.001
<0.001
0.02
<0.001

2045 (1845, 2266)

68 (62, 74)
21 (19, 23)
1.3 (1.1, 1.4)
10.0 (9.4, 10.6)

1434 (1143, 1798)

29 (24, 36)
6 (5, 8)
0.5 (0.4, 0.7)
9.8 (8.6, 11.2)

1.4 (1.1, 1.8)

2.3 (1.8, 2.8)
3.4 (2.5, 4.5)
2.5 (1.8, 3.5)
1.0 (0.9, 1.2)

0.007
<0.001
<0.001
<0.001
0.78

26.1 (23.9, 28.4)

16.0 (13.3, 19.3)

1.6 (1.3, 2.0)

<0.001

7.6 (6.9, 8.4)

6.7 (5.4, 8.4)

1.1 (0.9, 1.5)

0.32

Conversion factors to SI units: T and uT 3.467 (nmol/liter), DHEAS 0.002714 (mol/liter), glucose 0.0551 (mmol/liter), insulin 7.175
(pmol/liter).
a
P value reported from ANCOVA. Boldface indicates a statistically significant finding.
b
Not adjusted for age and BMI.
c
Sample sizes are n 79 for PCOS and n 12 for controls. Only subjects with glucose and insulin data that were complete at all time points
from the OGTT were included.

the criteria of at least one ovary greater than 10 cm3 and/or

PCOM. By morphology alone the majority of women with
PCOS (74 of 88 or 84%) had polycystic ovaries. Of the 21
control women, the vast majority (19 of 21 or 90%) had
normal-appearing ovaries by morphology alone on ultrasound. Only two control women had polycystic ovaries on
ultrasound by morphology. Thus, the odds of women with
PCOS having PCOM on ultrasound were elevated 50-fold,

FIG. 1. Scattergram distribution of

ISI0,120 by ovarian morphology in
women with PCOS and control. The
horizontal lines represent the mean
ISIs.

compared with controls (odds ratio 50; 95% CI 10 240; P

0.0001). PCOV was present in 81% of our group of women
with PCOS (71 of 88) but was more common in the control
women (48%) than PCOM. Despite this, the odds of having
a PCOV was significantly elevated in women with PCOS,
compared with controls (odds ratio 4.6, 95% CI 1.712.6, P
0.003). Thus, PCOM was a better discriminator than PCOV
between PCOS and control women.

2574

J Clin Endocrinol Metab, May 2005, 90(5):25712579

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).
Furthermore, we compared these same reproductive and
metabolic parameters between women with PCOV with
women without PCOV within the PCOS and controls separately (Table 3). 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.
We investigated the relationship between these same parameters and total ovarian volume both in the control women
and the women with PCOS, without regard to morphology
(Table 4). 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

Legro et al. PCO Morphology in PCOS

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).
Discussion

We found no association between either the morphology

or size of the ovary and any parameter of insulin action or
with T levels. These data suggest that the morphology and
size of the ovaries are of little value in identifying distinctive
metabolic or reproductive abnormalities in women with the
endocrine syndrome of PCOS. Nonetheless, polycystic ovaries were highly and significantly prevalent (compared with
our control group), although not invariably present in
women with PCOS. In fact, abnormal ovarian morphology
was significantly less common in the majority of control
women selected on the basis of normal reproductive and
metabolic parameters.
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

TABLE 2. Model-based estimates adjusting for age and BMI for indices of glucose metabolism, reproductive hormones, and other
ultrasound parameters according to ultrasound morphology of the ovaries in women with PCOS
Variable

Age (yr)b
BMI (kg/m2)b
OGTT parameters
Fasting glucose (mg/dl)
Fasting insulin (U/ml)
Fasting glucose to insulin ratio
Glucose 2 h (mg/dl)
Insulin 2 h (U/ml)
Integrated glucosec
Integrated insulinc
ISI0,120 from OGTT
Hormonal parameters
DHEAS (ng/ml)
T (ng/dl)
uT (ng/dl)
LH to FSH ratio
FSH (mIU/ml)
Ultrasound parameters
Total ovarian volume (right left
ovarian volume) (cm3)
Endometrial thickness (mm)

PCOS plus PCOM

(n 74)
[mean (95% CI)]

PCOS minus PCOM

(n 14)
[mean (95% CI)]

Ratio of PCOS plus

PCOM to PCOS minus
PCOM (95% CI)

27.2 (26.0, 28.5)

35.4 (33.4, 37.4)

30.3 (27.3, 33.7)

34.0 (29.9, 38.7)

0.9 (0.8, 1.0)

1.0 (0.9, 1.2)

0.06
0.58

92 (89, 94)
22 (20, 24)
4.2 (3.8, 4.6)
129 (121, 137)
112 (94, 132)
16,546 (15,743, 17,379)
12,939 (11,379, 14,714)
50 (46, 54)

96 (89, 103)
27 (21, 34)
3.6 (2.8, 4.5)
145 (126, 167)
143 (96, 213)
18,043 (16,201, 20,094)
15,105 (11,396, 20,021)
41 (34, 50)

1.0 (0.9, 1.0)

0.8 (0.6, 1.1)
1.2 (0.9, 1.5)
0.9 (0.8, 1.0)
0.8 (0.5, 1.2)
0.9 (0.8, 1.0)
0.9 (0.6, 1.2)
1.2 (1.0, 1.5)

0.29
0.15
0.24
0.14
0.27
0.15
0.33
0.10

1,980 (1,770, 2,216)

67 (61, 73)
21 (19, 23)
1.2 (1.1, 1.4)
9.6 (9.1, 10.2)

2,540 (1,953, 3,303)

68 (55, 85)
24 (19, 31)
1.2 (0.9, 1.6)
11.9 (10.4, 13.5)

0.8 (0.6, 1.0)

1.0 (0.8, 1.2)
0.9 (0.6, 1.1)
1.0 (0.7, 1.5)
0.8 (0.7, 0.9)

0.09
0.85
0.30
0.80
0.005

26.4 (24.1, 29.0)

23.4 (18.7, 29.1)

1.1 (0.9, 1.4)

0.31

7.6 (6.8, 8.5)

8.4 (6.5, 10.9)

0.9 (0.7, 1.2)

0.49

P valuea

Conversion factors to SI units: T and uT 3.467 (nmol/liter), DHEAS 0.002714 (mol/liter), glucose 0.0551 (mmol/liter), insulin 7.175
(pmol/liter).
a
P value reported from ANCOVA. Boldface indicates a statistically significant finding.
b
Not adjusted for age and BMI.
c
Sample sizes are n 65 for PCOM and n 14 for non-PCOM. Only subjects with glucose and insulin data that were complete at all time
points from the OGTT were included.

PCOS plus PCOV

(n 71)
[mean (95% CI)]
PCOS minus PCOV
(n 17)
[mean (95% CI)]

0.32
0.86
0.49
0.58
0.72
0.63
0.14
0.67
0.11
0.34
0.62
0.08
0.07
0.02
0.05
<0.001
0.15

0.9 (0.9, 1.1)

1.0 (0.9, 1.2)
1.0 (0.9, 1.0)
0.9 (0.7, 1.2)
1.0 (0.8, 1.3)
1.0 (0.8, 1.1)
0.7 (0.5, 1.1)
1.0 (0.9, 1.1)
0.8 (0.6, 1.1)
1.1 (0.9, 1.4)
0.9 (0.7, 1.2)
1.2 (1.0, 1.5)
1.3 (1.0, 1.6)
1.4 (1.1, 1.9)
0.9 (0.8, 1.0)
2.1 (1.8, 2.4)
1.2 (0.9, 1.5)

Ratio of PCOS
plus PCOV to
P valuea
PCOS minus PCOV
(95% CI)

86 (82, 91)
13 (10, 15)
6.9 (5.7, 8.3)

31.2 (26.1, 37.4)

26.0 (23.2, 29.1)

Control minus PCOV

(n 11)
[mean (95% CI)]

8.3 (6.7, 10.4)

21.5 (18.9, 24.4)

1,282 (963, 1,706)

30 (23, 39)
6 (4, 9)
0.5 (0.3, 0.8)
9.7 (7.9, 11.9)

4.9 (4.0, 6.1)

12.8 (11.4, 14.5)

1,496 (1,140, 1,965)

31 (24, 39)
5 (3, 8)
0.7 (0.5, 1.1)
10.3 (8.5, 12.5)

83 (71, 98)
93 (80, 108)
33 (21, 52)
34 (22, 52)
12,517 (10,159, 15,424) 12,381 (10,697, 14,331)
6,357 (3,703, 10,911)
6,040 (4,137, 8,819)
100 (83, 120)
90 (75, 107)

83 (79, 88)
13 (11, 16)
6.5 (5.3, 7.9)

27.6 (22.8, 33.4)

25.6 (22.8, 28.8)

Control plus PCOV

(n 10)
[mean (95% CI)]

Control

1.7 (1.2, 2.3)

1.7 (1.4, 2.0)

0.9 (0.6, 1.3)

1.0 (0.7, 1.4)
1.1 (0.6, 2.1)
0.7 (0.4, 1.3)
0.9 (0.7, 1.2)

0.9 (0.7, 1.1)

1.0 (0.5, 1.8)
1.0 (0.8, 1.3)
1.1 (0.5, 2.1)
1.1 (0.9, 1.5)

1.0 (0.9, 1.0)

1.0 (0.8, 1.3)
0.9 (0.7, 1.2)

0.9 (0.7, 1.1)

1.0 (0.8, 1.2)

0.002

<0.001

0.43
0.86
0.71
0.28
0.64

0.31
0.94
0.92
0.86
0.40

0.41
0.83
0.66

0.34
0.85

Ratio of control
plus PCOV to
P valuea
control minus
PCOV (95% CI)

Conversion factors to SI units: T and uT 3.467 (nmol/liter), DHEAS 0.002714 (mol/liter), glucose 0.0551 (mmol/liter), insulin 7.175 (pmol/liter).
P value reported from ANCOVA. Boldface indicates a statistically significant finding.
b
Not adjusted for age and BMI.
c
Sample sizes for PCOS are n 64 for PCOV and n 15 for non-PCOV. Sample sizes for control are n 4 for PCOV and n 8 for non-PCOV. Only subjects with glucose and
insulin data that were complete at all time points from the OGTT were included.

Age (yr)b
27.4 (26.1, 28.7)
28.9 (26.2, 31.9)
BMI (kg/m2)b
35.2 (33.3, 37.3)
34.8 (31.0, 39.1)
OGTT parameters
Fasting glucose (mg/dl)
92 (89, 95)
94 (88, 100)
Fasting insulin (U/ml)
22 (20, 25)
24 (19, 30)
Fasting glucose
4.1 (3.7, 4.5)
3.9 (3.2, 4.8)
to insulin ratio
Glucose 2 h (mg/dl)
131 (123, 139)
135 (119, 154)
Insulin 2 h (U/ml)
110 (92, 130)
147 (103, 209)
c
Integrated glucose
16,724 (15,910, 17,581) 17,138 (15,451, 19,009)
Integrated insulinc
12,710 (11,186, 14,441) 16,136 (12,380, 21,031)
49 (45, 54)
45 (37, 53)
ISI0,120 from OGTT
Hormonal parameters
DHEAS (ng/ml)
2,034 (1,811, 2,285)
2,172 (1,712, 2,756)
T (ng/dl)
70 (63, 76)
58 (48, 70)
uT (ng/dl)
22 (20, 25)
18 (14, 22)
LH to FSH ratio
1.3 (1.1, 1.5)
0.9 (0.7, 1.2)
FSH (mIU/ml)
9.7 (9.2, 10.3)
11.1 (9.8, 12.5)
Ultrasound parameters
Total ovarian volume
29.8 (27.9, 31.9)
14.5 (12.6, 16.7)
(right left ovarian
3
volume) (cm )
Endometrial thickness
8.0 (7.2, 9.0)
6.7 (5.3, 8.4)
(mm)

Variable

PCOS

TABLE 3. Model-based estimates adjusting for age and BMI for indices of glucose metabolism, reproductive hormones, and other ultrasound parameters according to ovarian
volume (PCOV at least one ovary 10 cm3) within women with PCOS and within controls

Legro et al. PCO Morphology in PCOS

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Legro et al. PCO Morphology in PCOS

TABLE 4. Spearman partial correlation coefficients adjusting for age and BMI between total ovarian volume and indices of glucose
metabolism, reproductive hormones, and other ultrasound parameters according to diagnosis (PCOS/control)
Variable
a

Age (yr)
BMI (yr)a
OGTT parameters
Fasting glucose
Fasting insulin
Fasting glucose to insulin ratio
Glucose 2 h
Insulin 2 h
Integrated glucoseb
Integrated insulinb
ISI0,120 from OGTT
Hormonal parameters
DHEAS
T
uT
LH to FSH ratio
FSH (mIU/ml)
Ultrasound parameters
Endometrial thickness

PCOS Spearman partial

correlation coefficient (95% CI)

P value

Control Spearman partial

correlation coefficient (95% CI)

P value

0.08 (0.30, 0.14)

0.13 (0.34, 0.09)

0.44
0.22

0.46 (0.76, 0.01)

0.07 (0.39, 0.51)

0.04
0.75

0.21 (0.42, 0.01)

0.06 (0.29, 0.16)
0.01 (0.22, 0.23)
0.01 (0.22, 0.24)
0.03 (0.25, 0.20)
0.06 (0.30, 0.18)
0.06 (0.29, 0.18)
0.03 (0.20, 0.25)

0.05
0.56
0.95
0.92
0.78
0.58
0.61
0.79

0.30 (0.68, 0.21)

0.04 (0.45, 0.51)
0.20 (0.62, 0.31)
0.11 (0.56, 0.38)
0.09 (0.41, 0.54)
0.34 (0.81, 0.41)
0.41 (0.84, 0.34)
0.19 (0.32, 0.61)

0.21
0.87
0.42
0.64
0.72
0.34
0.24
0.45

0.03 (0.25, 0.20)

0.16 (0.06, 0.37)
0.17 (0.05, 0.38)
0.19 (0.03, 0.40)
0.25 (0.45, 0.03)

0.79
0.13
0.11
0.07
0.02

0.27 (0.66, 0.24)

0.11 (0.56, 0.38)
0.17 (0.60, 0.33)
0.45 (0.76, 0.04)
0.31 (0.69, 0.19)

0.26
0.64
0.48
0.05
0.19

0.14 (0.09, 0.35)

0.19

0.36 (0.14, 0.71)

0.13

Boldface indicates a statistically significant finding.

a
Spearman correlation used, not adjusted for age and BMI.
b
Correlation based on sample size of n 79 for PCOS and n 12 for controls. Only subjects with glucose and insulin data that were complete
at all time points from the OGTT were included.

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, 3133). 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

FIG. 2. Correlation between ISI0,120

and total ovarian volume in women
with PCOS and controls. The regression
lines are not adjusted for age and BMI.

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

Legro et al. PCO Morphology in PCOS

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2577

FIG. 3. Correlation between total T and total ovarian volume in women with PCOS and control. The regression lines are not adjusted for age
and BMI. Conversion factors to SI units: T 3.467 (nmol/liter).

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 29
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 29 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

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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 womens 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 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

Legro et al. PCO Morphology in PCOS

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.
Acknowledgments
Received February 9, 2004. Accepted February 3, 2005.
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@psu.edu.
This work was supported by Grant PHS K24 HD01476 (to R.S.L.), the
National Cooperative Program in Infertility Research Grant U54
HD34449, and a General Clinical Research Center Grant MO1 RR 10732
and construction Grant C06 RR016499 to Pennsylvania State University.

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