Asymptomatic volunteers with a polycystic ovary are a functionally distinct but heterogeneous population.
Journal: 2009/May - Journal of Clinical Endocrinology and Metabolism
ISSN: 1945-7197
Abstract:
OBJECTIVE
Our objective was to determine the ovarian function of asymptomatic volunteers with a polycystic ovary (V-PCO).
METHODS
Non-hirsute eumenorrheic V-PCO (n = 32) and volunteers with ultrasonographically normal ovaries (V-NO) (n = 21) were compared with one another and with polycystic ovary syndrome (PCOS) patients who met National Institute of Health criteria (n = 90). DESIGN/SETTING/INTERVENTIONS: GnRH agonist (GnRHag), ACTH, and oral glucose tolerance tests were prospectively performed in a General Clinical Research Center.
RESULTS
The distribution of 17-hydroxyprogesterone (17OHP) responses to GnRHag of V-PCO formed a distinct population intermediate between that of V-NO, the reference population, and PCOS. Nevertheless, the V-PCO population was heterogeneous. There were 53% (seventeen of 32) that were functionally normal, with 17OHP responses and free testosterone levels like V-NO. A total of 25% (eight of 32) had an elevated free testosterone, thus meeting Rotterdam criteria for PCOS; one third of these had 17OHP hyperresponsiveness to GnRHag testing. The remaining 22% (seven of 32) had 17OHP hyperresponsiveness to GnRHag, but normal free testosterone. Of PCOS, 69% had elevated 17OHP hyperresponsiveness to GnRHag. Ovarian volume correlated significantly with 17OHP responses only in PCOS, accounting for just 10% of the variance.
CONCLUSIONS
Many asymptomatic volunteers have a PCO. They are a distinct, but heterogeneous, population with respect to ovarian function, ranging from normal (53%) to occult PCOS by Rotterdam criteria (25%). Nearly one quarter (22%) had the typical PCOS type of ovarian dysfunction without hyperandrogenemia, termed a "dysregulated PCO"; they or their offspring may be at risk for PCOS. Ovarian ultrasonographic characteristics must be considered when establishing norms for ovarian function.
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J Clin Endocrinol Metab 94(5): 1579-1586

Asymptomatic Volunteers with a Polycystic Ovary Are a Functionally Distinct but Heterogeneous Population

Subjects and Methods

Study subjects

There were 58 eumenorrheic healthy volunteers, 11.1–39.9 yr of age, recruited by advertisement from 2000–2007; they did not have hirsutism (maximum Ferriman-Gallwey score was five) (14), inflammatory acne that required systemic treatment, or a history of infertility. They were studied in the midfollicular phase (d 4–10) of their cycle; five were found to be preovulatory subjects and so were excluded post hoc. Half of the remainder had an elevated body mass index (BMI), more than 25 kg/m, but none had severe acanthosis nigricans (15). A total of 36% was adolescents, 11.1–17.5 yr of age and 1.1–3.8 yr post-menarche, who were eumenorrheic by adult standards and had been previously reported (16); 46% were non-Hispanic Black, 42% non-Hispanic white, and 12% Hispanic. These volunteers were classified post hoc into those with normal ovaries (V-NO) (n = 21, 36% adolescents) and V-PCO (n = 32, 44% adolescents).

A total of 99 consecutively consenting patients with anovulatory symptoms and an elevated plasma free testosterone on outpatient evaluation was recruited after excluding hyperprolactinemia, Cushing’s syndrome, and thyroid dysfunction. They were studied according to the protocol in Study protocol, when amenorrheic and off hormonal treatment for 2 months or more. After post hoc exclusion of eight who were found to be in the preovulatory or luteal phase of a menstrual cycle and three with nonclassical 21-hydroxylase-deficient congenital adrenal hyperplasia diagnosed by ACTH test criteria, the study group consisted of 88 patients 12.4–37.5 yr of age who met National Institute of Health criteria for PCOS (2). Ovarian morphology was not used as a diagnostic criterion. A total of 96% had secondary amenorrhea and 4% primary amenorrhea; 52% had hirsutism or inflammatory acne requiring systemic treatment (in equal numbers), 29% had both, and 19% had neither. There were 56% that were adolescents 12–18 yr of age; 41% were non-Hispanic Black, 52% were non-Hispanic white, 5% were Hispanic, and 2% were Asian.

These studies were approved by the University of Chicago Institutional Review Board, and were performed after obtaining informed consent from patients or parents and assent of minors.

Study protocol

All subjects were admitted to the University of Chicago General Clinical Research Center according to a previously reported protocol (16). Briefly, at 0745–0800 h, a fasting blood sample was drawn for baseline steroids, then at 0800–1000 h, an oral glucose tolerance test was performed according to American Diabetes Association guidelines, during which time blood was sampled at 15-min intervals for 2 h to determine mean baseline gonadotropin levels. Afterwards a pelvic ultrasound examination was performed. Dexamethasone 0.25 mg/m orally was administered at 1200 h to attenuate spontaneous adrenal steroid secretion. At 1600 h a basal sample was obtained for steroids, then a low-dose ACTH1–24 test (1.0 μg/1.73 m) was performed. At 1800 h, GnRHag (leuprolide acetate, 10 μg/kg sc) testing was begun after obtaining basal samples for gonadotropins at 15-min intervals for 1 h. Sampling was continued 0.5–18 h later; dexamethasone was then readministered at 1200 h to attenuate coincidental adrenocortical secretion, and sampling was completed at 20, 22, and 24 h after GnRHag.

Laboratory and procedural methods

Plasma total testosterone and dehydroepiandrosterone (DHEA) sulfate (DHEAS) were measured by commercially available kits (Diagnostic Products Corp., Los Angeles, CA). Free testosterone and SHBG binding capacity were calculated from a binding assay as previously reported (17,18). The cortisol assay was changed September 1, 2004, from a Diagnostic Products kit to an automated immunometric method (Immulite 2000; Diagnostic Products). The data were converted to Immulite values according to linear regression analysis of samples assayed by both methods. Estradiol was assayed by a sensitive immunoassay (Pantex, Santa Monica, CA) (18). Steroid intermediates (17OHP, androstenedione, 11-deoxycortisol, 17-hydroxypregnenolone, and DHEA) were measured by previously reported RIAs (19). Values below sensitivity levels were set to assay limits of sensitivity for purposes of statistical analyses, as indicated in Table 33 where pertinent. LH and FSH were measured by immunofluorometric assays (Delphia, Wallach, Finland). Plasma glucose was measured using a glucose analyzer (YSI Model 2300 STAT; Yellow Springs Instrument Inc., Yellow Springs, OH). Serum insulin was initially assayed by a double-antibody RIA in which the cross-reactivity of proinsulin was approximately 40% (20); the method was changed to Immulite assay in 2004. The data were converted to Immulite values according to linear regression analysis of samples assayed by both methods. Insulin resistance was indexed by homeostatic model assessment (HOMA) (21) and composite insulin sensitivity index (22) after exclusion of hemolyzed samples.

Table 3

GnRHag test results

GroupLH (U/liter)
FSH (U/liter)
Basal0.5 h1 h4 h18 h24 hBasal0.5 h1 h4 h18 h24 h
PCOS8.4 ± 4.8a31 ± 21a34 ± 23b79 ± 4448 ± 35a23 ± 11c5.0 ± 1.27.6 ± 2.38.4 ± 3.2c18 ± 8.5a13 ± 6.2a9.6 ± 4.6a
V-PCO4.1 ± 1.9d16 ± 7.1d23 ± 23e66 ± 2845 ± 2028 ± 135.0 ± 1.47.4 ± 1.98.6 ± 2.324 ± 8.4d22 ± 15f14 ± 3.9d
V-NO3.7 ± 1.917 ± 1022 ± 1466 ± 3330 ± 15g27 ± 115.4 ± 1.78.5 ± 2.310 ± 3.230 ± 1319 ± 6.414 ± 4.8
(5–95%)(0.2–6.4)(5.3–35)(9.7–48)(28–134)(17–55)(6.8–35)(3.4–7.9)(5.0–12)(5.4–15)(13–48)(11–27)(7.9–20)
Estradiol (pg/ml)
Progesterone (ng/dl)
17OHP (ng/dl)
Basal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreaseh
PCOS52 ± 24313 ± 254a293 ± 131a243 ± 132a26 ± 7.5c58 ± 50a57 ± 50a31 ± 49a48 ± 25a221 ± 182a240 ± 200a193 ± 189a
V-PCO47 ± 22216 ± 78f216 ± 78d169 ± 78d25 ± 2.050 ± 6153 ± 5936 ± 7226 ± 4.4d112 ± 43d121 ± 52d95 ± 51d
V-NO50 ± 27160 ± 69170 ± 66i125 ± 68i25 ± 0.229 ± 8.628 ± 8.9i4.7 ± 9.0i25 ± 0.2i76 ± 28j74 ± 29j49 ± 29j
(5–95%)(16–92)(66–261)(81–174)(33–166)(<25)(≤25–41)(≤25–41)(≤17)(<25)(33–122)(33–116)(9–92)
DHEA (ng/dl)
Androstenedione (ng/dl)
Testosterone (ng/dl)
Basal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreaseh
PCOS212 ± 105a270 ± 174a209 ± 74a−3 ± 96135 ± 57a203 ± 104a210 ± 104a75 ± 65a49 ± 26a63 ± 34a59 ± 35a11 ± 28b
V-PCO185 ± 75279 ± 194164 ± 58d−21 ± 5172 ± 23d101 ± 24d97 ± 20d25 ± 23d20 ± 8.3d26 ± 8.2d23 ± 8.8d2.7 ± 7.4e
V-NO143 ± 36g235 ± 145142 ± 52−1 ± 3758 ± 19i88 ± 3786 ± 3828 ± 2815 ± 6.1i21 ± 8.9i16 ± 5.8g1.0 ± 4.9
(5–95%)(98–192)(91–466)(71–195)(≤48)(33–89)(47–161)(54–178)(1–91)(<10–23)(<10–35)(<10–26)(≤9)

Values are presented as mean ± sd (5–95th percentile V-NO). A low dose of dexamethasone was given 4 h before the basal sample and immediately after the 18- h sample. All steroid intermediate levels increased significantly in response to GnRHag-induced increases in gonadotropins, except DHEA, which like cortisol decreased in response to dexamethasone administered after the 18-h sample. Conversion to International System of Units: progesterone × 0.0318 = nmol/liter, and DHEA × 0.0347 = nmol/liter.

P < 0.001 (PCOS vs. V-NO).
P < 0 .01 (PCOS vs. V-NO).
P < 0.05 (PCOS vs. V-NO).
P < 0.001 (V-PCO vs. PCOS).
P < 0.05 (V-PCO vs. PCOS).
P < 0.01 (V-PCO vs. PCOS).
P < 0.01 (V-NO vs. V-PCO).
Peak 20–24 h after GnRHag and its increase from basal.
P < 0.05 (V-NO vs. V-PCO).
P < 0.001 (V-NO vs. V-PCO).

Real-time pelvic ultrasound imaging was performed by the abdominal route in adolescents and intravaginal in adults using an Acuson Sequoia with a 4 MHz transducer (Acuson, Mountain View, CA) and a General Electric Voluson 730 5-9 MHz transducer (General Electric Co., Fairfield, CT), respectively, according to the manufacturers’ specifications, using standard algorithms and a phantom probe for periodic calibration. A uniform report form was used for all studies; the sonograms in adolescents were performed by one of two experienced pediatric radiologists and those in adults by one of three experienced gynecological ultrasonographers. A PCO was defined by modified Rotterdam criteria (23): an ovary that was polycystic sized [volume >10.5 cc in adults and >10.8 cc in adolescents (16) calculated by the formula for a prolate ellipsoid] and/or polyfollicular [≥10 follicles in the maximum plane (24)].

Data analyses

Normalcy of data distribution was evaluated by the Shapiro-Wilk W test. Logarithmic transformation was performed as necessary for normalization of data distribution. Comparisons among groups were performed by ANOVA with post hoc Fisher’s protected least differences test. Categorical variables were compared among groups by Fisher’s exact test (25). Correlations were determined from linear regression analysis. Results are reported as mean ± sem unless otherwise noted.

Demographical and hormonal measures obtained in adolescents and adults in each group were pooled after finding no significant differences in baseline PCOS features (total or free testosterone, androstenedione, 17OHP, and LH levels; PCO morphology); peak 17OHP, estradiol, LH, and FSH responses to GnRHag were likewise similar. The primary comparisons were between V-NO, designated as the normal reference group, and V-PCO. Hyperandrogenemia was defined as plasma free testosterone more than the 95th percentile of V-NO, which equaled 2.25 sd values above the mean after excluding an outlier value more than 3 sd values above the mean. 17OHP hyperresponsiveness to GnRHag was defined as the peak level above the observed V-NO range, which extended 2.25 sd values above the mean.

Study subjects

There were 58 eumenorrheic healthy volunteers, 11.1–39.9 yr of age, recruited by advertisement from 2000–2007; they did not have hirsutism (maximum Ferriman-Gallwey score was five) (14), inflammatory acne that required systemic treatment, or a history of infertility. They were studied in the midfollicular phase (d 4–10) of their cycle; five were found to be preovulatory subjects and so were excluded post hoc. Half of the remainder had an elevated body mass index (BMI), more than 25 kg/m, but none had severe acanthosis nigricans (15). A total of 36% was adolescents, 11.1–17.5 yr of age and 1.1–3.8 yr post-menarche, who were eumenorrheic by adult standards and had been previously reported (16); 46% were non-Hispanic Black, 42% non-Hispanic white, and 12% Hispanic. These volunteers were classified post hoc into those with normal ovaries (V-NO) (n = 21, 36% adolescents) and V-PCO (n = 32, 44% adolescents).

A total of 99 consecutively consenting patients with anovulatory symptoms and an elevated plasma free testosterone on outpatient evaluation was recruited after excluding hyperprolactinemia, Cushing’s syndrome, and thyroid dysfunction. They were studied according to the protocol in Study protocol, when amenorrheic and off hormonal treatment for 2 months or more. After post hoc exclusion of eight who were found to be in the preovulatory or luteal phase of a menstrual cycle and three with nonclassical 21-hydroxylase-deficient congenital adrenal hyperplasia diagnosed by ACTH test criteria, the study group consisted of 88 patients 12.4–37.5 yr of age who met National Institute of Health criteria for PCOS (2). Ovarian morphology was not used as a diagnostic criterion. A total of 96% had secondary amenorrhea and 4% primary amenorrhea; 52% had hirsutism or inflammatory acne requiring systemic treatment (in equal numbers), 29% had both, and 19% had neither. There were 56% that were adolescents 12–18 yr of age; 41% were non-Hispanic Black, 52% were non-Hispanic white, 5% were Hispanic, and 2% were Asian.

These studies were approved by the University of Chicago Institutional Review Board, and were performed after obtaining informed consent from patients or parents and assent of minors.

Study protocol

All subjects were admitted to the University of Chicago General Clinical Research Center according to a previously reported protocol (16). Briefly, at 0745–0800 h, a fasting blood sample was drawn for baseline steroids, then at 0800–1000 h, an oral glucose tolerance test was performed according to American Diabetes Association guidelines, during which time blood was sampled at 15-min intervals for 2 h to determine mean baseline gonadotropin levels. Afterwards a pelvic ultrasound examination was performed. Dexamethasone 0.25 mg/m orally was administered at 1200 h to attenuate spontaneous adrenal steroid secretion. At 1600 h a basal sample was obtained for steroids, then a low-dose ACTH1–24 test (1.0 μg/1.73 m) was performed. At 1800 h, GnRHag (leuprolide acetate, 10 μg/kg sc) testing was begun after obtaining basal samples for gonadotropins at 15-min intervals for 1 h. Sampling was continued 0.5–18 h later; dexamethasone was then readministered at 1200 h to attenuate coincidental adrenocortical secretion, and sampling was completed at 20, 22, and 24 h after GnRHag.

Laboratory and procedural methods

Plasma total testosterone and dehydroepiandrosterone (DHEA) sulfate (DHEAS) were measured by commercially available kits (Diagnostic Products Corp., Los Angeles, CA). Free testosterone and SHBG binding capacity were calculated from a binding assay as previously reported (17,18). The cortisol assay was changed September 1, 2004, from a Diagnostic Products kit to an automated immunometric method (Immulite 2000; Diagnostic Products). The data were converted to Immulite values according to linear regression analysis of samples assayed by both methods. Estradiol was assayed by a sensitive immunoassay (Pantex, Santa Monica, CA) (18). Steroid intermediates (17OHP, androstenedione, 11-deoxycortisol, 17-hydroxypregnenolone, and DHEA) were measured by previously reported RIAs (19). Values below sensitivity levels were set to assay limits of sensitivity for purposes of statistical analyses, as indicated in Table 33 where pertinent. LH and FSH were measured by immunofluorometric assays (Delphia, Wallach, Finland). Plasma glucose was measured using a glucose analyzer (YSI Model 2300 STAT; Yellow Springs Instrument Inc., Yellow Springs, OH). Serum insulin was initially assayed by a double-antibody RIA in which the cross-reactivity of proinsulin was approximately 40% (20); the method was changed to Immulite assay in 2004. The data were converted to Immulite values according to linear regression analysis of samples assayed by both methods. Insulin resistance was indexed by homeostatic model assessment (HOMA) (21) and composite insulin sensitivity index (22) after exclusion of hemolyzed samples.

Table 3

GnRHag test results

GroupLH (U/liter)
FSH (U/liter)
Basal0.5 h1 h4 h18 h24 hBasal0.5 h1 h4 h18 h24 h
PCOS8.4 ± 4.8a31 ± 21a34 ± 23b79 ± 4448 ± 35a23 ± 11c5.0 ± 1.27.6 ± 2.38.4 ± 3.2c18 ± 8.5a13 ± 6.2a9.6 ± 4.6a
V-PCO4.1 ± 1.9d16 ± 7.1d23 ± 23e66 ± 2845 ± 2028 ± 135.0 ± 1.47.4 ± 1.98.6 ± 2.324 ± 8.4d22 ± 15f14 ± 3.9d
V-NO3.7 ± 1.917 ± 1022 ± 1466 ± 3330 ± 15g27 ± 115.4 ± 1.78.5 ± 2.310 ± 3.230 ± 1319 ± 6.414 ± 4.8
(5–95%)(0.2–6.4)(5.3–35)(9.7–48)(28–134)(17–55)(6.8–35)(3.4–7.9)(5.0–12)(5.4–15)(13–48)(11–27)(7.9–20)
Estradiol (pg/ml)
Progesterone (ng/dl)
17OHP (ng/dl)
Basal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreaseh
PCOS52 ± 24313 ± 254a293 ± 131a243 ± 132a26 ± 7.5c58 ± 50a57 ± 50a31 ± 49a48 ± 25a221 ± 182a240 ± 200a193 ± 189a
V-PCO47 ± 22216 ± 78f216 ± 78d169 ± 78d25 ± 2.050 ± 6153 ± 5936 ± 7226 ± 4.4d112 ± 43d121 ± 52d95 ± 51d
V-NO50 ± 27160 ± 69170 ± 66i125 ± 68i25 ± 0.229 ± 8.628 ± 8.9i4.7 ± 9.0i25 ± 0.2i76 ± 28j74 ± 29j49 ± 29j
(5–95%)(16–92)(66–261)(81–174)(33–166)(<25)(≤25–41)(≤25–41)(≤17)(<25)(33–122)(33–116)(9–92)
DHEA (ng/dl)
Androstenedione (ng/dl)
Testosterone (ng/dl)
Basal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreasehBasal18 h20–24 hhIncreaseh
PCOS212 ± 105a270 ± 174a209 ± 74a−3 ± 96135 ± 57a203 ± 104a210 ± 104a75 ± 65a49 ± 26a63 ± 34a59 ± 35a11 ± 28b
V-PCO185 ± 75279 ± 194164 ± 58d−21 ± 5172 ± 23d101 ± 24d97 ± 20d25 ± 23d20 ± 8.3d26 ± 8.2d23 ± 8.8d2.7 ± 7.4e
V-NO143 ± 36g235 ± 145142 ± 52−1 ± 3758 ± 19i88 ± 3786 ± 3828 ± 2815 ± 6.1i21 ± 8.9i16 ± 5.8g1.0 ± 4.9
(5–95%)(98–192)(91–466)(71–195)(≤48)(33–89)(47–161)(54–178)(1–91)(<10–23)(<10–35)(<10–26)(≤9)

Values are presented as mean ± sd (5–95th percentile V-NO). A low dose of dexamethasone was given 4 h before the basal sample and immediately after the 18- h sample. All steroid intermediate levels increased significantly in response to GnRHag-induced increases in gonadotropins, except DHEA, which like cortisol decreased in response to dexamethasone administered after the 18-h sample. Conversion to International System of Units: progesterone × 0.0318 = nmol/liter, and DHEA × 0.0347 = nmol/liter.

P < 0.001 (PCOS vs. V-NO).
P < 0 .01 (PCOS vs. V-NO).
P < 0.05 (PCOS vs. V-NO).
P < 0.001 (V-PCO vs. PCOS).
P < 0.05 (V-PCO vs. PCOS).
P < 0.01 (V-PCO vs. PCOS).
P < 0.01 (V-NO vs. V-PCO).
Peak 20–24 h after GnRHag and its increase from basal.
P < 0.05 (V-NO vs. V-PCO).
P < 0.001 (V-NO vs. V-PCO).

Real-time pelvic ultrasound imaging was performed by the abdominal route in adolescents and intravaginal in adults using an Acuson Sequoia with a 4 MHz transducer (Acuson, Mountain View, CA) and a General Electric Voluson 730 5-9 MHz transducer (General Electric Co., Fairfield, CT), respectively, according to the manufacturers’ specifications, using standard algorithms and a phantom probe for periodic calibration. A uniform report form was used for all studies; the sonograms in adolescents were performed by one of two experienced pediatric radiologists and those in adults by one of three experienced gynecological ultrasonographers. A PCO was defined by modified Rotterdam criteria (23): an ovary that was polycystic sized [volume >10.5 cc in adults and >10.8 cc in adolescents (16) calculated by the formula for a prolate ellipsoid] and/or polyfollicular [≥10 follicles in the maximum plane (24)].

Data analyses

Normalcy of data distribution was evaluated by the Shapiro-Wilk W test. Logarithmic transformation was performed as necessary for normalization of data distribution. Comparisons among groups were performed by ANOVA with post hoc Fisher’s protected least differences test. Categorical variables were compared among groups by Fisher’s exact test (25). Correlations were determined from linear regression analysis. Results are reported as mean ± sem unless otherwise noted.

Demographical and hormonal measures obtained in adolescents and adults in each group were pooled after finding no significant differences in baseline PCOS features (total or free testosterone, androstenedione, 17OHP, and LH levels; PCO morphology); peak 17OHP, estradiol, LH, and FSH responses to GnRHag were likewise similar. The primary comparisons were between V-NO, designated as the normal reference group, and V-PCO. Hyperandrogenemia was defined as plasma free testosterone more than the 95th percentile of V-NO, which equaled 2.25 sd values above the mean after excluding an outlier value more than 3 sd values above the mean. 17OHP hyperresponsiveness to GnRHag was defined as the peak level above the observed V-NO range, which extended 2.25 sd values above the mean.

Results

Baseline studies

V-PCO resembled V-NO in all baseline characteristics other than having significantly greater ovarian size and elevated plasma free testosterone (Table 11).). Ovarian morphology of V-PCO was diverse: 29 met PCO size criteria, and eight of these and three others were polyfollicular. The percentage of adults who had been pregnant and the average parity did not differ significantly between the groups (V-NO 57% and 1.0, V-PCO 50% and 1.07, respectively). The groups did not differ significantly in HOMA or the insulin sensitivity index (V-NO 4.41 ± 0.61, V-PCO 6.13 ± 0.83). Two of the V-PCO and two of the V-NO subjects had impaired glucose tolerance.

Table 1

Baseline study group characteristics

Group (n)Age (yr)BMI (kg/m)Max ov (cc)Total T (ng/dl)Free T (pg/ml)17OHP (ng/dl)AND (ng/dl)SHBG (nm)DHEAS (μg/dl)E2 (pg/ml)LH (U/liter)FSH (U/liter)HOMA
PCOS (90)19.6 ± 0.7a35.5 ± 1.1a15 ± 1.0b66 ± 2.6b21 ± 1.0b61 ± 3.4c178 ± 8.1b14 ± 1.2b129 ± 8a49 ± 2.37.2 ± 0.5a4.9 ± 0.16.9 ± 0.8c
V-PCO (32)22.9 ± 1.4d25.3 ± 0.9e14 ± 1.134 ± 2.5e7.9 ± 0.8e36 ± 2.5e96 ± 4.5e29 ± 1.9e105 ± 1144 ± 3.23.8 ± 0.3e4.9 ± 1.41.9 ± 0.3e
V-NO (21)24.5 ± 2.027.1 ± 1.77.5 ± 0.5f27 ± 2.75.9 ± 0.6g41 ± 5.8g88 ± 7.128 ± 2.481 ± 947 ± 5.13.5 ± 0.35.6 ± 042.5 ± 0.4
Normal range3.3–10.615–533.0–9.022–8951–16511–4737–15419–851.5–5.63.6–7.90.7–5.4h

Values are presented as mean ± sem. The normal range is 5–95th percentile of V-NO group. Conversions to International System of Units: testosterone (T) × 0.0347 = nmol/liter, 17OHP × 0.0303 = nmol/liter, androstenedione (AND) × 0.0349 = nmol/liter, DHEAS × 0.0271 = μmol/liter, and estradiol (E2) × 3.61 = pmol/liter. Max ov, Maximal ovary size.

P < 0.01 (PCOS vs. V-NO).
P < 0.001 (PCOS vs. V-NO).
P < 0.05 (PCOS vs. V-NO).
P < 0.05 (V-PCO vs. PCOS).
P < 0.001 (V-PCO vs. PCOS).
P < 0.001 (V-NO vs. V-PCO).
P < 0.05 (V-NO vs. V-PCO).
Normal range for HOMA excludes subjects with impaired glucose tolerance; range is mean ± 2 sd values (n = 16).

Eight (25%) of V-PCO had hyperandrogenemia; thus, they met Rotterdam criteria for PCOS (hyperandrogenemia and a PCO), although they were eumenorrheic and asymptomatic (Fig. 11 and Table 22).). One of these had impaired glucose tolerance and a low HOMA; none had an elevated HOMA or low-insulin sensitivity index.

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Object name is zeg0050964780001.jpg

The distribution of baseline plasma free testosterone and peak 17OHP responses to GnRHag testing in each study group. A, Plasma free testosterone distribution was significantly skewed to the right in all groups (P < 0.01). That of the V-PCO population was significantly higher than that of V-NO (P < 0.05), with 25% being above the V-NO 95th percentile of 9 pg/ml. B, 17OHP peak distribution was normally distributed in both volunteer groups, but positively skewed in PCOS. The 17OHP peak of V-PCO was intermediate between V-NO and PCOS, and significantly different from both (P < 0.001). The peak 17OHP of V-PCO was above that of V-NO in 31% conversely; that of PCOS was in the V-NO range in 31%.

Table 2

Phenotype of V-PCO who had biochemical evidence of ovarian dysfunction

Age (yr)BMI (kg/m)WC (cm)Max Ov (cc)PolyfollicularFree T (pg/ml)Peak 17OHP (ng/dl)SHBG (nm)DHEAS (μg/dl)HOMA
Subclinical PCOS, Rotterdam criteria (n = 8)
 No. 117.425.381.022.41266131843.0
 No. 219.030.795.011.915134142243.5
 No. 319.623.670.512.212138351740.9
 No. 423.431.392.011.6+13200131391.7
 No. 533.232.683.016.3+10164232771.5
 No. 635.226.884.012.6+1017427902.1
 No. 735.525.985.024.92511825580.5a
 No. 836.722.281.04.2+15101411030.4
 Mean (sem)27.5 (3.0)27.3 (1.4)83.9 (2.6)14.5 (2.3)14.0 (1.7)137 (15)23.8 (3.7)156 (26)1.7 (0.4)
Dysregulated PCO (n = 7)
 No. 911.922.877.513.951522447
 No. 1012.418.767.015.5515636514.0
 No. 1112.924.373.512.3624821314.1a
 No. 1214.923.371.512.0618843612.4
 No. 1319.020.770.018.9+42624492
 No. 1423.720.475.012.18146361100.6
 No. 1535.231.490.017.2519634562.1
 Mean (sem)18.0 (3.2)23.0 (1.4)74.9 (2.8)14.6 (1.0)5.6 (0.5)193 (18)34.0 (3.3)64 (10)2.6 (0.7)
P value0.0480.0480.0380.90.160.0010.0330.0010.0090.3

Also see Table 11.. Max Ov, Maximal ovary size; T, testosterone; WC, waist circumference.

Impaired glucose tolerance.

PCOS patients had the expected significantly higher androgen and LH levels, larger ovarian size, lower SHBG, and higher BMI than the volunteer groups (Table 11 and Fig. 11).). Although they were younger on average than the volunteers, their age ranges were similar, and reanalysis after controlling for age did not alter any conclusions. There was no relationship between plasma free testosterone and ovarian volume (Fig. 22)) or type of PCO. Glucose abnormalities (impaired glucose tolerance and five cases of asymptomatic type 2 diabetes mellitus) were more prevalent in PCOS (24%) than in V-NO (10%) (P < 0.01). The HOMA index of insulin resistance was higher (P < 0.05), and the composite insulin sensitivity index was lower (2.88 ± 0.30; P < 0.05), than that of both volunteer groups.

An external file that holds a picture, illustration, etc.
Object name is zeg0050964780002.jpg

Correlations of ovarian volume to androgenic ovarian function. A, Baseline plasma free testosterone was not correlated to ovarian volume in any group. B, Peak 17OHP response to GnRHag challenge correlated with ovarian volume only in PCOS (r = 0.324).

GnRHag test

V-PCO constituted a distinct population with respect to 17OHP responsiveness to GnRHag. The peak 17OHP response to GnRHag was significantly greater than that of V-NO, yet significantly less than that of PCOS (Fig. 11).). The absolute increase in 17OHP in response to GnRHag was greater in magnitude than that of any other steroid and 2-fold higher in V-PCO than V-NO (Table 33).). This was paralleled by a lower and less consistent, but significant, difference in the progesterone responses of these two groups. The 17OHP responses of volunteers were not related to ovarian volume (Fig. 22)) or baseline free testosterone (Fig. 33).). In addition to 17OHP and progesterone, V-PCO also had significant, but less striking, PCOS-like abnormalities in LH and estradiol responses to GnRHag.

An external file that holds a picture, illustration, etc.
Object name is zeg0050964780003.jpg

Scatterplot of peak 17OHP responses to GnRHag in relationship to early-morning plasma free testosterone levels of eumenorrheic healthy volunteers. The dotted line shows the upper limits of normal for V-NO (one V-NO outlier had asymptomatic hyperandrogenemia). V-PCO are in four subgroups: types A and B (25% of V-PCO) fit Rotterdam criteria for PCOS, although asymptomatic, with the B type additionally having the typical PCOS type of ovarian dysfunction (17OHP hyperresponsiveness to GnRHag). Type C (22% of V-PCO) has a “dysregulated PCO” without hyperandrogenemia. Type D (53%) has ovarian function that is within normal limits.

However, the V-PCO population was heterogeneous with respect to endocrine function, consisting of four functional subgroups (Fig. 33).). As noted previously, eight (25% of V-PCO) were hyperandrogenemic, thus meeting Rotterdam criteria for PCOS, although asymptomatic. Five of this cadre had normal 17OHP responses to GnRHag testing (Fig. 3A3A),), whereas three had elevated responses (Fig. 3B3B).). On the other hand, seven V-PCO (22% of V-PCO) with17OHP hyperresponsiveness to GnRHag lacked hyperandrogenemia (Fig. 3C3C);); these are designated as having a “dysregulated PCO.” Their average 17OHP peak was at the median for PCOS (Fig. 11).). The V-PCO subgroup that met Rotterdam criteria for asymptomatic PCOS was significantly older (median age 28.3 vs. 14.9 yr), had significantly higher BMI, waist circumference, and DHEAS, as well as a lower SHBG level, than the dysregulated PCO subgroup, although their 17OHP responses to GnRHag testing were slightly less (Table 22).). The majority of V-PCO (53%) had endocrine function that was within normal limits (Fig. 3D3D).

PCOS responses were significantly different from those of both volunteer groups in the expected ways. The great majority (69%) had an elevated 17OHP peak in response to GnRHag (Fig. 11 and Table 33),), and their distribution of 17OHP responses was right skewed, with a broad tail of overlap (30%) with V-NO (Fig. 11).). Their increase in 17OHP was significantly greater than that of both V-NO and V-PCO. The peak 17OHP of PCOS correlated with baseline free testosterone levels (r = 0.501; P < 0.001; data not shown). Peak 17OHP responses of PCOS also correlated modestly with ovarian volume (r = 0.324; P < 0.002) (Fig. 22).

There were no significant differences in baseline characteristics or pituitary-ovarian function among PCOS patients subgrouped according to the type of ovarian morphology, other than those attributable to a modest correlation of peak estradiol with ovarian size in the overall group (r = 0.392; P < 0.001). For example, peak 17OHP averaged 210 ± 41, 194 ± 33, 224 ± 24, and 307 ± 51 ng/dl, respectively, in those lacking a PCO (n = 21), those with only polyfollicular morphology (n = 13), or those with only polycystic-sized ovaries (n = 32) or with both PCO features (n = 24).

ACTH test

Steroid androgenic intermediate (e.g. DHEA, androstenedione, 17OHP) responses to ACTH of V-PCO, as a whole or by subgroup, were similar those of V-NO, whereas their androgenic responses were significantly less than those of PCOS (data not shown).

Baseline studies

V-PCO resembled V-NO in all baseline characteristics other than having significantly greater ovarian size and elevated plasma free testosterone (Table 11).). Ovarian morphology of V-PCO was diverse: 29 met PCO size criteria, and eight of these and three others were polyfollicular. The percentage of adults who had been pregnant and the average parity did not differ significantly between the groups (V-NO 57% and 1.0, V-PCO 50% and 1.07, respectively). The groups did not differ significantly in HOMA or the insulin sensitivity index (V-NO 4.41 ± 0.61, V-PCO 6.13 ± 0.83). Two of the V-PCO and two of the V-NO subjects had impaired glucose tolerance.

Table 1

Baseline study group characteristics

Group (n)Age (yr)BMI (kg/m)Max ov (cc)Total T (ng/dl)Free T (pg/ml)17OHP (ng/dl)AND (ng/dl)SHBG (nm)DHEAS (μg/dl)E2 (pg/ml)LH (U/liter)FSH (U/liter)HOMA
PCOS (90)19.6 ± 0.7a35.5 ± 1.1a15 ± 1.0b66 ± 2.6b21 ± 1.0b61 ± 3.4c178 ± 8.1b14 ± 1.2b129 ± 8a49 ± 2.37.2 ± 0.5a4.9 ± 0.16.9 ± 0.8c
V-PCO (32)22.9 ± 1.4d25.3 ± 0.9e14 ± 1.134 ± 2.5e7.9 ± 0.8e36 ± 2.5e96 ± 4.5e29 ± 1.9e105 ± 1144 ± 3.23.8 ± 0.3e4.9 ± 1.41.9 ± 0.3e
V-NO (21)24.5 ± 2.027.1 ± 1.77.5 ± 0.5f27 ± 2.75.9 ± 0.6g41 ± 5.8g88 ± 7.128 ± 2.481 ± 947 ± 5.13.5 ± 0.35.6 ± 042.5 ± 0.4
Normal range3.3–10.615–533.0–9.022–8951–16511–4737–15419–851.5–5.63.6–7.90.7–5.4h

Values are presented as mean ± sem. The normal range is 5–95th percentile of V-NO group. Conversions to International System of Units: testosterone (T) × 0.0347 = nmol/liter, 17OHP × 0.0303 = nmol/liter, androstenedione (AND) × 0.0349 = nmol/liter, DHEAS × 0.0271 = μmol/liter, and estradiol (E2) × 3.61 = pmol/liter. Max ov, Maximal ovary size.

P < 0.01 (PCOS vs. V-NO).
P < 0.001 (PCOS vs. V-NO).
P < 0.05 (PCOS vs. V-NO).
P < 0.05 (V-PCO vs. PCOS).
P < 0.001 (V-PCO vs. PCOS).
P < 0.001 (V-NO vs. V-PCO).
P < 0.05 (V-NO vs. V-PCO).
Normal range for HOMA excludes subjects with impaired glucose tolerance; range is mean ± 2 sd values (n = 16).

Eight (25%) of V-PCO had hyperandrogenemia; thus, they met Rotterdam criteria for PCOS (hyperandrogenemia and a PCO), although they were eumenorrheic and asymptomatic (Fig. 11 and Table 22).). One of these had impaired glucose tolerance and a low HOMA; none had an elevated HOMA or low-insulin sensitivity index.

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The distribution of baseline plasma free testosterone and peak 17OHP responses to GnRHag testing in each study group. A, Plasma free testosterone distribution was significantly skewed to the right in all groups (P < 0.01). That of the V-PCO population was significantly higher than that of V-NO (P < 0.05), with 25% being above the V-NO 95th percentile of 9 pg/ml. B, 17OHP peak distribution was normally distributed in both volunteer groups, but positively skewed in PCOS. The 17OHP peak of V-PCO was intermediate between V-NO and PCOS, and significantly different from both (P < 0.001). The peak 17OHP of V-PCO was above that of V-NO in 31% conversely; that of PCOS was in the V-NO range in 31%.

Table 2

Phenotype of V-PCO who had biochemical evidence of ovarian dysfunction

Age (yr)BMI (kg/m)WC (cm)Max Ov (cc)PolyfollicularFree T (pg/ml)Peak 17OHP (ng/dl)SHBG (nm)DHEAS (μg/dl)HOMA
Subclinical PCOS, Rotterdam criteria (n = 8)
 No. 117.425.381.022.41266131843.0
 No. 219.030.795.011.915134142243.5
 No. 319.623.670.512.212138351740.9
 No. 423.431.392.011.6+13200131391.7
 No. 533.232.683.016.3+10164232771.5
 No. 635.226.884.012.6+1017427902.1
 No. 735.525.985.024.92511825580.5a
 No. 836.722.281.04.2+15101411030.4
 Mean (sem)27.5 (3.0)27.3 (1.4)83.9 (2.6)14.5 (2.3)14.0 (1.7)137 (15)23.8 (3.7)156 (26)1.7 (0.4)
Dysregulated PCO (n = 7)
 No. 911.922.877.513.951522447
 No. 1012.418.767.015.5515636514.0
 No. 1112.924.373.512.3624821314.1a
 No. 1214.923.371.512.0618843612.4
 No. 1319.020.770.018.9+42624492
 No. 1423.720.475.012.18146361100.6
 No. 1535.231.490.017.2519634562.1
 Mean (sem)18.0 (3.2)23.0 (1.4)74.9 (2.8)14.6 (1.0)5.6 (0.5)193 (18)34.0 (3.3)64 (10)2.6 (0.7)
P value0.0480.0480.0380.90.160.0010.0330.0010.0090.3

Also see Table 11.. Max Ov, Maximal ovary size; T, testosterone; WC, waist circumference.

Impaired glucose tolerance.

PCOS patients had the expected significantly higher androgen and LH levels, larger ovarian size, lower SHBG, and higher BMI than the volunteer groups (Table 11 and Fig. 11).). Although they were younger on average than the volunteers, their age ranges were similar, and reanalysis after controlling for age did not alter any conclusions. There was no relationship between plasma free testosterone and ovarian volume (Fig. 22)) or type of PCO. Glucose abnormalities (impaired glucose tolerance and five cases of asymptomatic type 2 diabetes mellitus) were more prevalent in PCOS (24%) than in V-NO (10%) (P < 0.01). The HOMA index of insulin resistance was higher (P < 0.05), and the composite insulin sensitivity index was lower (2.88 ± 0.30; P < 0.05), than that of both volunteer groups.

An external file that holds a picture, illustration, etc.
Object name is zeg0050964780002.jpg

Correlations of ovarian volume to androgenic ovarian function. A, Baseline plasma free testosterone was not correlated to ovarian volume in any group. B, Peak 17OHP response to GnRHag challenge correlated with ovarian volume only in PCOS (r = 0.324).

GnRHag test

V-PCO constituted a distinct population with respect to 17OHP responsiveness to GnRHag. The peak 17OHP response to GnRHag was significantly greater than that of V-NO, yet significantly less than that of PCOS (Fig. 11).). The absolute increase in 17OHP in response to GnRHag was greater in magnitude than that of any other steroid and 2-fold higher in V-PCO than V-NO (Table 33).). This was paralleled by a lower and less consistent, but significant, difference in the progesterone responses of these two groups. The 17OHP responses of volunteers were not related to ovarian volume (Fig. 22)) or baseline free testosterone (Fig. 33).). In addition to 17OHP and progesterone, V-PCO also had significant, but less striking, PCOS-like abnormalities in LH and estradiol responses to GnRHag.

An external file that holds a picture, illustration, etc.
Object name is zeg0050964780003.jpg

Scatterplot of peak 17OHP responses to GnRHag in relationship to early-morning plasma free testosterone levels of eumenorrheic healthy volunteers. The dotted line shows the upper limits of normal for V-NO (one V-NO outlier had asymptomatic hyperandrogenemia). V-PCO are in four subgroups: types A and B (25% of V-PCO) fit Rotterdam criteria for PCOS, although asymptomatic, with the B type additionally having the typical PCOS type of ovarian dysfunction (17OHP hyperresponsiveness to GnRHag). Type C (22% of V-PCO) has a “dysregulated PCO” without hyperandrogenemia. Type D (53%) has ovarian function that is within normal limits.

However, the V-PCO population was heterogeneous with respect to endocrine function, consisting of four functional subgroups (Fig. 33).). As noted previously, eight (25% of V-PCO) were hyperandrogenemic, thus meeting Rotterdam criteria for PCOS, although asymptomatic. Five of this cadre had normal 17OHP responses to GnRHag testing (Fig. 3A3A),), whereas three had elevated responses (Fig. 3B3B).). On the other hand, seven V-PCO (22% of V-PCO) with17OHP hyperresponsiveness to GnRHag lacked hyperandrogenemia (Fig. 3C3C);); these are designated as having a “dysregulated PCO.” Their average 17OHP peak was at the median for PCOS (Fig. 11).). The V-PCO subgroup that met Rotterdam criteria for asymptomatic PCOS was significantly older (median age 28.3 vs. 14.9 yr), had significantly higher BMI, waist circumference, and DHEAS, as well as a lower SHBG level, than the dysregulated PCO subgroup, although their 17OHP responses to GnRHag testing were slightly less (Table 22).). The majority of V-PCO (53%) had endocrine function that was within normal limits (Fig. 3D3D).

PCOS responses were significantly different from those of both volunteer groups in the expected ways. The great majority (69%) had an elevated 17OHP peak in response to GnRHag (Fig. 11 and Table 33),), and their distribution of 17OHP responses was right skewed, with a broad tail of overlap (30%) with V-NO (Fig. 11).). Their increase in 17OHP was significantly greater than that of both V-NO and V-PCO. The peak 17OHP of PCOS correlated with baseline free testosterone levels (r = 0.501; P < 0.001; data not shown). Peak 17OHP responses of PCOS also correlated modestly with ovarian volume (r = 0.324; P < 0.002) (Fig. 22).

There were no significant differences in baseline characteristics or pituitary-ovarian function among PCOS patients subgrouped according to the type of ovarian morphology, other than those attributable to a modest correlation of peak estradiol with ovarian size in the overall group (r = 0.392; P < 0.001). For example, peak 17OHP averaged 210 ± 41, 194 ± 33, 224 ± 24, and 307 ± 51 ng/dl, respectively, in those lacking a PCO (n = 21), those with only polyfollicular morphology (n = 13), or those with only polycystic-sized ovaries (n = 32) or with both PCO features (n = 24).

ACTH test

Steroid androgenic intermediate (e.g. DHEA, androstenedione, 17OHP) responses to ACTH of V-PCO, as a whole or by subgroup, were similar those of V-NO, whereas their androgenic responses were significantly less than those of PCOS (data not shown).

Discussion

We found that the peak 17OHP in response to GnRHag of asymptomatic eumenorrheic V-PCO was intermediate between those with normal ovaries (V-NO) and PCOS females, as have others (11,12,13). What we describe for the first time, to our knowledge, is that, whereas these women form a distinct population with respect to ovarian function (Fig. 11),), this population is functionally heterogeneous: it consists of distinct subgroups with a spectrum of ovarian function, ranging from normal ovarian endocrine function to subclinical PCOS, with an intermediate subgroup that has subclinical normoandrogenemic ovarian dysfunction.

Most asymptomatic V-PCO (53%) are in the first subgroup and are normal variants: testing showed normal ovarian function. At the other extreme, 25% of the total V-PCO group had hyperandrogenemia as well as a PCO, despite being eumenorrheic and asymptomatic, thus meeting Rotterdam criteria for PCOS. This finding is in agreement with a recent estimate of PCOS prevalence in unselected women with a PCO (6). Some of these with subclinical Rotterdam PCOSs had the typical PCOS type of ovarian dysfunction (three of eight), whereas the others did not (five of eight); this proportion is not significantly different than the percentage of PCOS patients (30%) lacking 17OHP hyperresponsiveness to GnRHag, which represents a unique type of ovarian dysfunction that is the subject of a companion study. Interestingly, 22% of V-PCO were in an intermediate subgroup that had 17OHP hyperresponsiveness to GnRHag without hyperandrogenemia, which we have termed a “dysregulated PCO.” They were significantly younger and leaner, and had significantly less PCOS-type biochemical abnormalities than the subclinical PCOS volunteer subgroup. None of these subgroups had significant adrenal androgenic dysfunction, compatible with the report of Chang et al. (12).

The reproductive significance of this heterogeneity is unclear. Groups of V-PCO women selected for normal ovulatory function have had the mild 17OHP hyperresponsiveness to GnRHag or human chorionic gonadotropin stimulation testing (12,13). Asymptomatic PCO morphology did not predict progression to clinical PCOS in 17 similar women followed from 30–38 yr of age (26). In one of these studies, total testosterone was elevated in 10%. However, the relationship of hyperandrogenemia to 17OHP abnormality in these studies is unclear. Although these reports suggest that the finding of a PCO in an asymptomatic woman is of no reproductive consequence, even if accompanied by biochemical evidence of ovarian dysfunction, the natural history is not clear in an unselected population.

The possibility has to be considered that subclinical Rotterdam-type PCOS or a dysregulated PCO indicates a type of PCO that is a risk factor for the development of symptoms under certain conditions or is a carrier state for PCOS. Evidence is accumulating that 17OHP hyperresponsiveness to a GnRHag test is a marker for the intrinsic ovarian dysregulation of PCOS (19,27). Even the dysregulated PCO is likely to indicate subclinical ovarian androgenic hyperfunction because theca cells from women with a PCO secrete excess androgen in vitro, regardless of PCOS symptomatology (28). The PCO of PCOS seems to be inherited as an autosomal dominant trait with variable penetrance, i.e. it is not necessarily associated with evidence of PCOS in mothers (29,30). These considerations are compatible with a complex trait hypothesis of PCOS. For example, an inherited PCOS type of theca cell dysfunction, manifest as a dysregulated PCO, may occur from a granulosa cell defect in the anti-müllerian hormone signaling system that normally restrains steroidogenesis and follicle antrum formation (31,32). PCOS symptomatology may then emerge in a subject with subclinical ovarian dysfunction if excess adiposity (26,33) and/or insulin resistance develops (34). The significantly greater age and BMI of our subclinical PCOS than of our dysregulated PCO subgroup are compatible with the dysregulated PCO being a potential precursor of PCOS. However, we did not find evidence of fasting or postprandial insulin resistance in our dysregulated PCO group, although the former was reported in one study (13).

Very little of the dysfunction of a PCO can be attributed to its size, even though ovarian volume is the major structural correlate of hyperandrogenism (1,5). Significant correlations between ovarian functional parameters and ovarian size were not found in either volunteer group. Furthermore, even though the 17OHP response to GnRHag correlates significantly with ovarian volume in PCOS, the correlation accounts for only about 10% of the variance, and all steroidogenic abnormalities are similar in those PCOS subjects with normal ovaries and those with each of the varying types of PCO morphology.

Therefore, it seems premature to consider a PCO truly normal, even though its prevalence is high among the general population and in eumenorrheic asymptomatic volunteers. The high prevalence of subclinical ovarian dysfunction in PCO (47%) must be considered in studies of ovarian function. We estimate the prevalence of the typical PCOS type of ovarian dysfunction as 69% based on the normal range of 17OHP responses to GnRHag testing of our V-NO group. The finding of Pasquali et al. (35) that 17OHP hyperresponsiveness to GnRHag was present in only a distinct minority (30%) of PCOS is apparently because they did not exclude asymptomatic V-PCO from their control group.

The main limitations of our study are that our volunteers may not be representative of the general population and that polycystic ovaries were identified, of necessity, by abdominal ultrasonography in adolescents, who comprised about one third of the volunteer groups. The prevalence of a PCO was greater in our volunteers than reported in the general population (8,9,10), although in line with that reported in some studies of adult volunteer populations (4,12). Thus, it is possible that a subtle, unreported concern may have led them to volunteer, yet was not clinically evident. Finally, whereas the presence of regular menstrual cyclicity in the general population ordinarily indicates normal ovulatory function, this is not necessarily the case in PCOS (6) and, thus, is not necessarily the case in the dysregulated PCO. Although ovulation has been documented in well-characterized V-PCO groups (11,12,13), the prevalence of ovulatory cycles among unselected women with a PCO relative to the infertility population is unknown.

In summary, whereas asymptomatic eumenorrheic volunteers form a distinct population with respect to ovarian function, this population is functionally heterogeneous, with nearly half having subclinical ovarian dysfunction. Longitudinal or family studies are warranted to determine whether the latter subjects are carriers of a PCO gene or are at risk for having anovulatory cycles. Another clinical research implication of this study is that the ultrasonographic characteristics of the ovary must be considered when establishing norms for ovarian function testing.

Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637
Address all correspondence and requests for reprints to: Robert L. Rosenfield, University of Chicago Hospitals, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, 5841 S. Maryland Avenue, (MC- 5053), Chicago, Illinois 60637. E-mail: ude.ogacihcu.dsb.sdep@sorbor.
Address all correspondence and requests for reprints to: Robert L. Rosenfield, University of Chicago Hospitals, Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, 5841 S. Maryland Avenue, (MC- 5053), Chicago, Illinois 60637. E-mail: ude.ogacihcu.dsb.sdep@sorbor.
Received 2008 Dec 23; Accepted 2009 Feb 17.

Abstract

Context/Objective: Our objective was to determine the ovarian function of asymptomatic volunteers with a polycystic ovary (V-PCO).

Participants: Non-hirsute eumenorrheic V-PCO (n = 32) and volunteers with ultrasonographically normal ovaries (V-NO) (n = 21) were compared with one another and with polycystic ovary syndrome (PCOS) patients who met National Institute of Health criteria (n = 90).

Design/Setting/Interventions: GnRH agonist (GnRHag), ACTH, and oral glucose tolerance tests were prospectively performed in a General Clinical Research Center.

Results: The distribution of 17-hydroxyprogesterone (17OHP) responses to GnRHag of V-PCO formed a distinct population intermediate between that of V-NO, the reference population, and PCOS. Nevertheless, the V-PCO population was heterogeneous. There were 53% (seventeen of 32) that were functionally normal, with 17OHP responses and free testosterone levels like V-NO. A total of 25% (eight of 32) had an elevated free testosterone, thus meeting Rotterdam criteria for PCOS; one third of these had 17OHP hyperresponsiveness to GnRHag testing. The remaining 22% (seven of 32) had 17OHP hyperresponsiveness to GnRHag, but normal free testosterone. Of PCOS, 69% had elevated 17OHP hyperresponsiveness to GnRHag. Ovarian volume correlated significantly with 17OHP responses only in PCOS, accounting for just 10% of the variance.

Conclusions: Many asymptomatic volunteers have a PCO. They are a distinct, but heterogeneous, population with respect to ovarian function, ranging from normal (53%) to occult PCOS by Rotterdam criteria (25%). Nearly one quarter (22%) had the typical PCOS type of ovarian dysfunction without hyperandrogenemia, termed a “dysregulated PCO”; they or their offspring may be at risk for PCOS. Ovarian ultrasonographic characteristics must be considered when establishing norms for ovarian function.

Abstract

The ovarian dysfunction of polycystic ovary (PCO) syndrome (PCOS) is typically due to functional ovarian hyperandrogenism, which is usually characterized by 17-hydroxyprogesterone (17OHP) hyperresponsiveness to GnRH agonist (GnRHag) testing (1). PCOS is commonly diagnosed as a disorder of otherwise unexplained hyperandrogenic anovulation (“National Institute of Health criteria”) (2). Most women with PCOS have a PCO (3,4). Because the ovarian dysfunction of PCOS may not be reflected in anovulatory symptoms, the alternative diagnostic “Rotterdam criterion” of a PCO with clinical or biochemical evidence of hyperandrogenism is widely accepted (5,6).

Many healthy volunteers have a PCO (4,7,8,9,10). Groups of such women have mild PCOS features, including a mild degree of the PCOS type of ovarian dysfunction that is intermediate between that of women with normal ovaries and that of PCOS (11,12,13). Here, we report that there is heterogeneity of ovarian function within the population of normal eumenorrheic volunteers with a PCO (V-PCO). About half have no evidence of ovarian endocrine dysfunction, whereas the others have a spectrum of subclinical endocrine dysfunction that includes PCOS.

Values are presented as mean ± sd (5–95th percentile V-NO). A low dose of dexamethasone was given 4 h before the basal sample and immediately after the 18- h sample. All steroid intermediate levels increased significantly in response to GnRHag-induced increases in gonadotropins, except DHEA, which like cortisol decreased in response to dexamethasone administered after the 18-h sample. Conversion to International System of Units: progesterone × 0.0318 = nmol/liter, and DHEA × 0.0347 = nmol/liter.

Values are presented as mean ± sem. The normal range is 5–95th percentile of V-NO group. Conversions to International System of Units: testosterone (T) × 0.0347 = nmol/liter, 17OHP × 0.0303 = nmol/liter, androstenedione (AND) × 0.0349 = nmol/liter, DHEAS × 0.0271 = μmol/liter, and estradiol (E2) × 3.61 = pmol/liter. Max ov, Maximal ovary size.

Also see Table 11.. Max Ov, Maximal ovary size; T, testosterone; WC, waist circumference.

Acknowledgments

We thank Kristen Kasza for biostatistical support, and Kate Feinstein and David Yousefzadeh for ultrasonographic support.

Acknowledgments

Footnotes

This research was supported in part by the Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Institutes of Health through cooperative agreement [U54-041859] as part of the Specialized Cooperative Centers Program in Reproduction and Infertility Research (to R.L.R.), HL-075079 (to D.A.E.), RR-00055, and UL1RR024999 from the National Center For Research Resources, and the Blum-Kovler Family Foundation (to D.A.E.).

Disclosure Summary: The authors have nothing to declare.

First Published Online February 24, 2009

Abbreviations: BMI, Body mass index; DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate; GnRHag, GnRH agonist; HOMA, homeostatic model assessment; 17OHP, 17-hydroxyprogesterone; PCO, polycystic ovary; PCOS, polycystic ovary syndrome; V-NO, volunteers with normal ovaries; V-PCO, volunteers with a polycystic ovary.

Footnotes
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