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Polycystic Ovarian Morphology in Normal Women Does Not Predict the Development of Polycystic Ovary Syndrome

Reproductive Endocrine Unit (M.K.M., J.E.H., J.M.A., C.K.W.), Department of Medicine, Massachusetts General Hospital, and MGH Biostatistics Center (H.L.), Massachusetts General Hospital, Boston, Massachusetts 02114; and Harvard Medical School (M.K.M.), Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: C. K. Welt, Reproductive Endocrine, BHX 511, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: cwelt{at}partners.org.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: Polycystic ovarian morphology (PCOM) is present in 25% of normal women in the absence of polycystic ovary syndrome (PCOS); however, the natural history of PCOM is unknown.

Objective: We hypothesized that the presence of PCOM predisposes the development of PCOS.

Design: The study was a longitudinal follow-up study over 8.2 ± 5.2 yr (mean ± SD; range 1.7–17.5 yr).

Setting: The study took place in an outpatient setting.

Subjects: Women who took part in a previous study as a normal control and had an ultrasound examination (n = 40) participated.

Intervention: Subjects underwent an interval menstrual history, physical exam, blood sampling, and repeat ultrasound in the follicular phase.

Main Outcome Measure: Development of PCOS was diagnosed by irregular menses and hyperandrogenism, in the absence of other disorders. Changes in ovarian morphology over time were evaluated.

Results: At the baseline visit, 23 women (57.5%) had PCOM and 17 (42.5%) had normal ovarian morphology. One subject with PCOM developed irregular menses and presumptive PCOS. Eleven subjects with PCOM no longer met the criteria for PCOM at follow-up. There was no factor that predicted the change to normal ovarian morphology at the follow-up visit.

Conclusions: These data suggest that PCOM in women with regular ovulatory cycles does not commonly predispose the development of PCOS. Although it is unusual to develop PCOM if the ovaries are normal on first assessment, ovaries in women with PCOM no longer meet the criteria for PCOM in approximately half of cases over time.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
POLYCYSTIC OVARY SYNDROME (PCOS) was initially named for the pathological appearance of the ovary in women with menstrual irregularities and hyperandrogenism (1). The appearance of the polycystic ovary on ultrasound was subsequently described (2). Nevertheless, a 1990 National Institutes of Health (NIH) conference suggested diagnostic criteria for PCOS that did not include ultrasound evidence of polycystic ovarian morphology (PCOM) (3). The recent Rotterdam European Society of Human Reproduction and Embryology (ESHRE)/American Society of Reproductive Medicine (ASRM)-sponsored PCOS consensus workshop group reemphasized the importance of PCOM in the diagnostic criteria (4). However, the inclusion of PCOM in the definition of PCOS remains controversial (5, 6). Indeed, whereas PCOM is found consistently in women with PCOS defined by oligomenorrhea and hyperandrogenism (7, 8), an identical ovarian morphology has been documented in 16–25% of normal women (9, 10, 11).

Several studies characterized nonhirsute, regularly cycling women with PCOM (12, 13, 14, 15). Ovulatory women with PCOM have testosterone and androstenedione levels that are increased in comparison with women who have normal ovarian morphology, although levels are generally within the normal range (13, 14). Two studies also demonstrated higher insulin levels in regularly cycling women with PCOM, compared with women who have normal ovarian morphology (14, 15). Differences in gonadotropin dynamics were also demonstrated in some (15) but not all studies (14). These findings suggest that ovulatory women with PCOM may be at the mildest end of the spectrum of PCOS. However, it is unknown whether women with PCOM and ovulatory cycles are at risk for the development of PCOS. Longitudinal studies examining the natural history of PCOM in regularly cycling women are necessary to determine whether the ovarian morphology is constant and whether it confers a propensity to later development of PCOS. If PCOM does predispose a woman to PCOS, longitudinal studies could help identify the environmental or age-related factors, such as weight gain or worsening insulin resistance, that precipitate the oligomenorrhea and overt hyperandrogenism that characterize PCOS.

Thus, to determine the longitudinal history of women with regular cycles and PCOM, we examined women with normal ovarian morphology and PCOM on ultrasound 1.7–17.5 yr after a previous examination. Menstrual history, anthropomorphic measures, metabolic parameters, and androgen and gonadotropin levels were also examined to determine the propensity for the development of PCOS at follow-up. These studies provide evidence that PCOM does not commonly predispose to the development of PCOS.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects were recruited from previous studies of regularly cycling women at the Massachusetts General Hospital Reproductive Endocrine Unit (n = 40). All of the studies were approved by the Institutional Review Board of the Massachusetts General Hospital. All subjects gave their written informed consent. To be eligible for recruitment, subjects were required to have a baseline ultrasound (performed by J.M.A.), with an interpretable follicle number and ovarian volume, during a study in which they participated as a control. The total number of eligible subjects was 177. Of this total number, 87 could not be located, seven were successfully contacted but did not respond to our request, 30 responded but did not participate, five were pregnant or breast-feeding, five were on oral contraceptives, one subject was deceased, and two subjects participated but had uninterpretable ultrasounds at the follow-up visit. At the time of the initial studies, all women were between the ages of 18 and 42 yr, with menstrual cycle lengths of 25–35 d, and were not taking any hormonal medications with the exception of stable thyroid replacement. All subjects had normal thyroid function and prolactin levels. All studies included a physical examination, estradiol and gonadotropin levels, and a transvaginal ovarian ultrasound or, rarely, a transabdominal ultrasound (n = 1). The initial pelvic ultrasounds were performed using an SAL 727B, 5-MHz convex array transducer (Toshiba, Tokyo, Japan). The subjects were not routinely informed about ovarian morphology nor were they counseled about possible treatment because PCOM was considered a normal variant (9, 10, 11). Approximately half of the subjects also had androgen levels available from the baseline examination (Tables 1–3), and the available data were distributed equally between groups.

Baseline and follow-up ultrasound scans were performed by the same ultrasonographer (J.M.A.) and multiple images were recorded for each ovary. Two reviewers (M.K.M. and C.K.W. or J.E.H.) read each ultrasound, blinded to both the reading of the other and subject name. Ovarian volume was calculated as length x width x height in centimeters multiplied by 0.5233, i.e. the formula for an ellipse (17). For both the baseline and follow-up ultrasound, PCOM was defined as at least one ovary with 12 or more follicles of 2–10 mm in a single plane or an ovarian volume greater than 10 ml in the absence of a dominant follicle greater than 10 mm, a corpus luteum, or a cyst (2, 4, 18). Ultrasound images not meeting these criteria were designated as normal. A consensus was reached on the reading of all ultrasounds by the reviewers.

PCOS was defined according to the NIH criteria as chronic oligomenorrhea (fewer than nine menstrual periods per year) and clinical and/or biochemical evidence of hyperandrogenism, in the absence of other disorders causing the same phenotype (3). Clinical hyperandrogenism was defined by an elevated Ferriman Gallwey score greater than 9, i.e. greater than the 95% confidence limit for a control population with regular menses and documented ovulation (7). Biochemical hyperandrogenism was defined as an androgen level greater than the 95% confidence limits in previously reported ovulatory control subjects: testosterone greater than 63 ng/ml (2.8 nmol/liter), dehydroepiandrosterone sulfate (DHEAS) greater than 430 µg/dl (1.16 µmol/liter), or androstenedione levels greater than 3.8 ng/ml (13.3 nmol/liter) (7).

Hormonal assays

Serum LH, FSH, and estradiol were measured in the Reproductive Endocrine Unit Reference Laboratory using a two-site monoclonal nonisotopic system (Axsym; Abbott Laboratories, Abbott Park, IL) (19). LH and FSH levels are expressed in international units per liter as equivalents of the Second International Reference Preparation 71/223 of human menopausal gonadotropins. Serum testosterone and androstenedione were measured using a RIA (Coat-a-Count; Diagnostic Products Corp., Los Angeles, CA) (14). 17-Hydroxyprogesterone was measured by RIA (20). SHBG was measured using a chemiluminescent enzyme immunometric assay (Immulite; Diagnostic Products Corp.) (14). Insulin was measured using an immunochemiluminescent immunoassay (Immulite 2000; Diagnostic Products Corp.). The lower limit of detection of the insulin assay was 2.0 µIU/ml.

Data analysis

Free testosterone was calculated using total testosterone and SHBG according to the formula of Vermeulen et al. (21). The homeostasis model assessment (HOMA) was used to estimate insulin resistance (22).

Data that were not normally distributed were log normalized for comparison. The average ovarian volume and maximum follicle number in both ovaries were used for analysis, excluding the volume of an ovary with a dominant follicle (>10 mm) or a corpus luteum. Age, anthropomorphic measurements, and hormones were compared at baseline and the follow-up visit between women with normal ovaries and PCOM using t tests. Age, anthropomorphic measurements, and hormones were also compared within subjects over time using paired t tests. Fisher’s exact test was used to compare the prevalence of metabolic syndrome, defined by the Adult Treatment Panel III criteria (23), between the two groups at the follow-up visit. A longitudinal logistic regression approach was used to predict the change from PCOM to normal ovarian morphology. Generalized estimating equations were used to estimate the regression parameters and their SEs under the assumption of an independent correlation structure (24). One-way ANOVA was used to examine differences between groups at the follow-up visit. Data are expressed as mean ± SEM, unless otherwise indicated. P < 0.05 was considered significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Baseline visit

At the initial visit, 23 subjects (57.5%) had PCOM, and 17 subjects (42.5%) had normal ovarian morphology. Women with PCOM tended to be slightly younger than women with normal ovaries (mean ± SD; 27.9 ± 5.4 vs. 32.0 ± 7.7 yr; P = 0.06). At baseline, women with PCOM and normal ovaries had similar body mass index (BMI), blood pressure, Ferriman Gallwey score, and gonadotropin levels (Table 1 and Fig. 1). Follicular phase testosterone was higher in women with PCOM, compared with those with normal ovarian morphology (P < 0.05). As expected, women with PCOM had a greater average ovarian volume (P < 0.01) and maximum number of follicles in a single plane (P < 0.001) than women with normal ovarian morphology, and endometrial thickness was thinner (P < 0.05).

View larger version (17K): [in this window] [in a new window]   FIG. 1. BMI, LH to FSH ratio, testosterone (T), and DHEAS in women with normal ovarian morphology (normal) and PCOM at baseline (black bars) and follow-up visits (white bars). Subjects were 29.7 ± 6.7 yr old (mean ± SD) at baseline and 37.9 ± 8.9 yr old at follow-up visits. Note that testosterone levels were available in only 19 subjects at baseline, and DHEAS in only 27 subjects at baseline. Of note, testosterone levels were significantly different between women with normal ovarian morphology and PCOM at baseline (P < 0.05). To convert to SI units, multiply testosterone by 0.035 and DHEAS by 0.02714. *, P < 0.05.

Follow-up visits occurred 1.7–17.5 yr after the first visit (mean ± SD, 8.2 ± 5.2 yr) (Table 2). Eighteen subjects were older than 40 yr old and three subjects were 50 yr old at their second visit. Four of the subjects, aged 45 and 48 yr, and two subjects aged 50 yr had irregular menses and/or an elevated FSH level in the postmenopausal range (>30 IU/liter) and one subject, aged 56 yr, was menopausal. Of note, all of these subjects were in the normal group at baseline and follow-up. These subjects were also older than subjects in the rest of the group at baseline (mean ± SD, 39.4 ± 3.5 vs. 28.3 ± 5.8 yr; P < 0.001) and follow-up (mean ± SD, 50.5 ± 4.2 vs. 36.1 ± 7.8 yr; P < 0.001), although the interval between visits was not different (mean ± SD, 11.1 ± 4.0 vs. 7.8 ± 5.2 yr; P = 0.2).

BMI, waist to hip ratio (WHR), and FSH increased and DHEAS decreased at the follow-up visit. The Ferriman Gallwey score and other hormonal parameters at the follow-up visit were not different from baseline (Table 2 and Fig. 1). In all subjects, the ovarian volume and maximum number of follicles in a single plane decreased, as did endometrial thickness.

If the five perimenopausal or menopausal women were removed from analysis, there was no longer a difference in the maximum number of follicles in a single plane (10.0 ± 0.6 vs. 9.0 ± 0.6; P = 0.2). However, the increase in BMI (23.5 ± 0.7 vs. 25.0 ± 0.9 kg/m²; P < 0.001), WHR (0.80 ± 0.02 vs. 0.86 ± 0.01; P < 0.001), and FSH levels (10.7 ± 0.5 vs. 12.6 ± 0.7 IU/liter; P < 0.05) remained, as did the decrease in DHEAS (172.0 ± 16.0 vs. 124.6 ± 11.7 µg/dl; 4.7 ± 0.4 vs. 3.4 ± 0.3 µmol/liter; P < 0.005) at the follow-up visit.

Follow-up visit: PCOM at baseline

One subject, aged 37 yr and with PCOM at baseline, developed irregular menses with weight gain from 102 to 136 kg during the 13-yr follow-up interval. Her physician diagnosed her with PCOS. Two years later, her menses became regular when she lost 13 kg. At the follow-up visit, her Ferriman Gallwey score had increased from 9 to 12, but she had normal androgen levels and menstrual cycles; therefore, a diagnosis of PCOS could not be confirmed using the NIH criteria (3). She also had normal ovarian morphology at follow-up, an FSH level on d 7 that was 16.6 IU/liter, greater than 1 SD above the mean for normal women (15.6 IU/liter), and a low LH to FSH ratio (0.5), which are not typical values in women with PCOS (7, 8, 25). Despite an 11- to 17-kg weight gain in four additional subjects, the remainder of the subjects continued to have regular menstrual cycles and none entered menopause.

Of the 23 subjects with PCOM at the first visit, 12 (52.2%) had PCOM at the second visit, and 11 (47.8%) no longer met the criteria for PCOM. Age and interval follow-up were not different between the two groups (Table 3). In subjects who no longer met the criteria for PCOM, there was a decrease in both average ovarian volume (12.5 ± 1.5 vs. 5.3 ± 0.8 ml; P < 0.05) and maximum number of follicles in a single plane (11.7 ± 0.8 vs. 6.1 ± 0.5; P < 0.001) between the baseline and follow-up visits, whereas there was no change in the average ovarian volume (13.7 ± 2.3 vs. 13.8 ± 1.8 ml; P = 0.4) or maximum number of follicles (11.7 ± 0.8 vs. 12.4 ± 0.9; P = 0.5) in subjects who continued to meet the criteria for PCOM at follow-up (Fig. 2). There was no factor that predicted the change from PCOM to normal ovarian morphology.

View larger version (14K): [in this window] [in a new window]   FIG. 2. Maximum follicle number in a single plane and average ovarian volume in regularly cycling women with normal ovarian morphology at baseline and follow-up (Nl Nl); PCOM at baseline and follow-up (PCOM PCOM); and PCOM at baseline and normal ovarian morphology at follow-up (PCOM Nl). *, P < 0.05.

Follow-up visit: normal ovarian morphology at baseline

All subjects with normal ovarian morphology at baseline maintained regular menstrual cycles except for the five subjects who were entering or in menopause, as discussed above. All subjects maintained normal ovarian morphology at follow-up (Fig. 2).

Follow-up visit: PCOM vs. normal ovaries at baseline

An interval history was taken to determine whether the presence of PCOM was related to infertility. In women with PCOM, 20 subjects had a pregnancy and no subjects reported infertility (Table 3). In women with normal ovarian morphology, 14 subjects had a pregnancy, but two of these subjects had a history of infertility and required medical intervention. One subject had infertility related to male factor and the other had infertility for unknown reasons. Three subjects with PCOM and four subjects with normal ovarian morphology did not attempt to become pregnant, and fertility could not be assessed.

To determine whether the presence of PCOM is associated with the development of cardiovascular risk factors over time, the follow-up anthropomorphic and metabolic features were compared between women with PCOM and normal morphology. There was no difference in BMI, WHR, blood pressure, fasting glucose, or insulin based on ovarian morphology at baseline or follow-up (Table 3). At follow-up, the glucose level 120 min after a 75-g glucose load was higher in women with PCOM at baseline and normal ovarian morphology at follow-up, compared with women who had normal ovarian morphology at both visits, even when controlled for age and weight. There was no difference in the prevalence of metabolic syndrome or any of its components between the two groups.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Previous data suggest that women with regular menstrual cycles, no evidence of hyperandrogenism, and PCOM on ultrasound have mildly increased androgens and insulin, compared with women with regular cycles and normal ovaries (13, 14). Furthermore, PCOM is a cardinal feature of PCOS defined as irregular menses and hyperandrogenism (7, 8, 25). Taken together, these findings suggested that PCOM may mark a predisposition for the future development of PCOS in regularly cycling women. On the contrary, the current data suggest that the presence of PCOM does not commonly predispose to PCOS because only one subject with PCOM developed irregular menses for an incidence of 4%. Thus, although characteristics of regularly cycling women with PCOM suggest they may constitute the mildest end of the spectrum of PCOS, PCOM in women with regular cycles is not a major risk factor for the development of PCOS.

An additional finding in this study is that 48% of subjects with PCOM at baseline failed to meet the criteria over time (4). This is not surprising in light of normal ovarian changes with aging. Our longitudinal results are consistent with cross-sectional ultrasound assessments in normal women (26, 27) and women with PCOS (28, 29, 30), which demonstrated a decrease in antral follicle number (>2 mm) with aging. These ultrasonographic changes coincide with the decreased antral follicle count in pathology specimens and may thus reflect the decrease in total follicle number during reproductive aging (31, 32, 33). There is also evidence that ovarian volume decreases in normal women over the age range studied (8, 34, 35). Although one previous study suggested that up to 44% of women with possible PCOS may have PCOM after menopause (36), the criteria used to assess PCOM were much less stringent than those used in the current study (4). All subjects in the current study who reached perimenopause had normal ovarian morphology at baseline and follow-up, even when applying the less stringent criteria (36).

Taken together, because the definition of PCOM proposed by the Rotterdam conference is dependent on follicle number and ovarian volume, it is not surprising that some ovaries had normal morphology on the second visit. Further longitudinal studies will be necessary to investigate the prevalence of PCOM in the menopausal transition in women with PCOM and/or PCOS at baseline.

Despite the potential effect of age on follicle number and ovarian volume, there were no differences at baseline or follow-up in age, follow-up interval, anthropomorphic, metabolic, or hormone measurements between women with PCOM at baseline who did or did not meet the criteria for PCOM at follow-up. It is possible that the study was not adequately powered to detect such differences between groups. In subjects with PCOM at baseline who were older than 35 yr of age at follow-up, five continued to meet the criteria for PCOM, whereas nine no longer met the criteria for PCOM. We cannot rule out the possibility that PCOM would be present on pathological examination or using an ultrasound able to resolve follicles less than 2 mm. However, within the resolution of the currently available ultrasound technology and using the Rotterdam definition of PCOM (4), aging appears to be associated with a failure to meet the criteria for PCOM. These findings suggest that age-based criteria may be necessary for the assessment of PCOM in older women.

At the baseline visit, normal cycling women with PCOM had a higher testosterone level than women with normal ovaries, similar to previous studies, but there was no difference in androstenedione, DHEAS, insulin, or HOMA (14, 15). The difference in the findings between the current study and previous studies may relate to the smaller number of subjects, absence of pooled blood samples from multiple draws, greater variation in the cycle day at the time of the study, or inclusion of women with hirsutism and regular menses. Clinically there was no apparent infertility in the group with PCOM. Finally, there were no differences in anthropomorphic or metabolic parameters that confer an increased risk of cardiovascular disease in the PCOM group, compared with the normal ovarian morphology group over time, with the exception of the higher glucose level after a glucose load in women who no longer met the criteria for PCOM at the follow-up visit, compared with women with normal ovarian morphology at both visits. Further longitudinal studies will be necessary to confirm this finding and evaluate its significance.

Importantly, women with hirsutism and regular menstrual cycles were not excluded from the study. Four of five of these women with hirsutism would be diagnosed with PCOS based on the Rotterdam criteria (4) but not the NIH criteria used in the current study (3). Although women with hyperandrogenism, PCOM, and regular menstrual cycles have been demonstrated to have higher insulin and HOMA, compared with control women in some studies (37, 38), none of the current subjects had an elevated fasting insulin or glucose, nor did they develop irregular menses during a follow-up of 2, 4, 6, and 16 yr. These findings provide evidence that progression to PCOS with irregular menses may not be the natural history of women with hyperandrogenism and PCOM.

It has been demonstrated that obesity is associated with a higher prevalence of menstrual cycle disorders in women with polycystic ovary morphology (39). There was an average increase in weight over time in all subjects in the current study. Furthermore, only one of five subjects with PCOM and weight gain between 11 and 20 kg developed PCOS. These findings suggest that weight gain in women with PCOM is not enough to promote the development of PCOS in the majority of cases.

The strengths of this study were the ability to study well-characterized women over time, the longitudinal ultrasound evaluation by a single ultrasonographer who took multiple images to provide the best source for analysis, and hormone assays performed using the same methodology in the same laboratory over time. The maximum number of follicles in a single plane was documented, replicating the technique used at the time of all initial studies and satisfying the requirement of the current PCOM definition (4). Ultrasound images were overread by two observers using published criteria (4) to prevent bias by a single observer. A limitation of the study is that ultrasound technology has improved with time (40), and thus, the resolution of small follicles is superior with new ultrasound imaging. The use of both volume and follicle number as criteria for determining PCOM ameliorates some of this bias because determination of ovarian volume is less subject to improvements in resolution than is the examination of small follicles. Furthermore, the trend for follicle number to decrease over time, consistent with previous studies across aging (26, 27), supports the findings of this study.

The key finding from this longitudinal study is that women with regular menstrual cycles and PCOM are not at significant risk for the development of PCOS. Rather, the normal decrease in follicle number with aging may result in a change from PCOM to normal ovarian morphology. Thus, PCOM identified using a strict definition may not be a constant ovarian feature over time and does not appear to predict the development of PCOS.

	Acknowledgments

 
We thank Joseph Moy, B.S., and Patrick Sluss, Ph.D., for their assay expertise. We also thank the subjects who willingly participated in this study after many years.

	Footnotes

 
This work was supported by the National Institutes of Health Grant U01 HD 4417 and National Center for Research Resources General Clinical Research Centers Program Grant M01-RR-01066.

Disclosure statement: J.E.H. consults for Novartis and Ferring. The other authors have nothing to disclose.

First Published Online August 1, 2006

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HOMA, homeostasis model assessment; PCOM, polycystic ovarian morphology; PCOS, polycystic ovary syndrome; WHR, waist to hip ratio.

Received May 19, 2006.

Accepted July 26, 2006.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Stein IF, Leventhal ML 1935 Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191
2. Adams J, Franks S, Polson DW, Mason HD, Abdulwahid N, Tucker M, Morris DV, Price J, Jacobs HS 1985 Multifollicular ovaries: clinical and endocrine features and response to pulsatile gonadotropin releasing hormone. Lancet 2:1375–1379[Medline]
3. Zawadzki JK, Dunaif A 1992 Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A, Givens JR, Haseltine FP, Merriam GR, eds. Polycystic ovary syndrome. Boston: Blackwell Scientific; 377–384
4. 2003 Revised consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS) 2004. Hum Reprod 19:41–47
5. Franks S 2006 Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: in defense of the Rotterdam criteria. J Clin Endocrinol Metab 91:786–789[Abstract/Free Full Text]
6. Azziz R 2006 Controversy in clinical endocrinology: diagnosis of polycystic ovarian syndrome: the Rotterdam criteria are premature. J Clin Endocrinol Metab 91:781–785[Abstract/Free Full Text]
7. Taylor AE, McCourt B, Martin KA, Anderson EJ, Adams JM, Schoenfeld DA, Hall JE 1997 Determinants of abnormal gonadotropin secretion in clinically defined women with polycystic ovary syndrome. J Clin Endocrinol Metab 82:2248–2256[Abstract/Free Full Text]
8. Legro RS, Chiu P, Kunselman AR, Bentley CM, Dodson WC, Dunaif A 2005 Polycystic ovaries are common in women with hyperandrogenic chronic anovulation but do not predict metabolic or reproductive phenotype. J Clin Endocrinol Metab 90:2571–2579[Abstract/Free Full Text]
9. Farquhar CM, Birdsall M, Manning P, Mitchell JM, France JT 1994 The prevalence of polycystic ovaries on ultrasound scanning in a population of randomly selected women. Aust NZ J Obstet Gynaecol 34:67–72[Medline]
10. Clayton RN, Ogden V, Hodgkinson J, Worswick L, Rodin DA, Dyer S, Meade TW 1992 How common are polycystic ovaries in normal women and what is their significance for the fertility of the population? Clin Endocrinol (Oxf) 37:127–134[Medline]
11. Polson DW, Adams J, Wadsworth J, Franks S 1988 Polycystic ovaries—a common finding in normal women. Lancet 1:870–872[CrossRef][Medline]
12. Norman RJ, Hague WM, Masters SC, Wang XJ 1995 Subjects with polycystic ovaries without hyperandrogenaemia exhibit similar disturbances in insulin and lipid profiles as those with polycystic ovary syndrome. Hum Reprod 10:2258–2261[Abstract/Free Full Text]
13. Carmina E, Wong L, Chang L, Paulson RJ, Sauer MV, Stanczyk FZ, Lobo RA 1997 Endocrine abnormalities in ovulatory women with polycystic ovaries on ultrasound. Hum Reprod 12:905–909[Abstract/Free Full Text]
14. Adams JM, Taylor AE, Crowley Jr WF, Hall JE 2004 Polycystic ovarian morphology with regular ovulatory cycles: insights into the pathophysiology of polycystic ovarian syndrome. J Clin Endocrinol Metab 89:4343–4350[Abstract/Free Full Text]
15. Chang PL, Lindheim SR, Lowre C, Ferin M, Gonzalez F, Berglund L, Carmina E, Sauer MV, Lobo RA 2000 Normal ovulatory women with polycystic ovaries have hyperandrogenic pituitary-ovarian responses to gonadotropin-releasing hormone-agonist testing. J Clin Endocrinol Metab 85:995–1000[Abstract/Free Full Text]
16. Ferriman D, Gallwey JD 1961 Clinical assessment of body hair growth in women. J Clin Endocrinol Metab 21:1440–1447[Medline]
17. Sample WF, Lippe BM, Gyepes MT 1977 Gray-scale ultrasonography of the normal female pelvis. Radiology 125:477–483[Abstract]
18. Jonard S, Robert Y, Cortet-Rudelli C, Pigny P, Decanter C, Dewailly D 2003 Ultrasound examination of polycystic ovaries: is it worth counting the follicles? Hum Reprod 18:598–603[Abstract/Free Full Text]
19. Welt CK, Pagan YL, Smith PC, Rado KB, Hall JE 2003 Control of follicle-stimulating hormone by estradiol and the inhibins: critical role of estradiol at the hypothalamus during the luteal-follicular transition. J Clin Endocrinol Metab 88:1766–1771[Abstract/Free Full Text]
20. Ibanez L, Hall JE, Potau H, Carrascosa A, Prat N, Taylor AE 1996 Ovarian 17-hydroxyprogesterone hyperresponsiveness to GnRH agonist challenge in women with polycystic ovary syndrome is not mediated by gonadotropin hypersecretion: evidence from GnRH agonist and human chorionic gonadotropin stimulation testing. J Clin Endocrinol Metab 81:4103–4107[Abstract/Free Full Text]
21. Vermeulen A, Verdonck L, Kaufman JM 1999 A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab 84:3666–3672[Abstract/Free Full Text]
22. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC 1985 Homeostasis model assessment: insulin resistance and ß-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419[CrossRef][Medline]
23. Grundy SM, Brewer B, Cleeman JI, Smith SC, Lenfant C 2004 Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association Conference on Scientific Issues Related to Definition. Circulation 109:433–438[Free Full Text]
24. Liang KY, Zeger SL 1986 Longitudinal data analysis using generalized linear models. Biometrika 73:13–22[Abstract/Free Full Text]
25. Carmina E, Koyama T, Chang L, Stanczyk FZ, Lobo RA 1992 Does ethnicity influence the prevalence of adrenal hyperandrogenism and insulin resistance in polycystic ovary syndrome? Am J Obstet Gynecol 167:1807–1812[Medline]
26. Ruess ML, Kline J, Santos R, Levin B, Timor-Tritsch I 1996 Age and the ovarian follicle pool assessed with transvaginal ultrasonography. Am J Obstet Gynecol 174:624–627[CrossRef][Medline]
27. Erdem A, Erdem M, Biberoglu K, Hayit O, Arslan M, Gursoy R 2002 Age-related changes in ovarian volume, antral follicle counts and basal FSH in women with normal reproductive health. J Reprod Med 47:835–839[Medline]
28. Bili H, Laven J, Imani B, Eijkemans MJ, Fauser BC 2001 Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenorrhoeic infertile women of reproductive years. Eur J Endocrinol 145:749–755[Abstract]
29. Elting MW, Kwee J, Korsen TJ, Rekers-Mombarg LT, Schoemaker J 2003 Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles. Fertil Steril 79:1154–1160[CrossRef][Medline]
30. Elting MW, Korsen TJ, Schoemaker J 2001 Obesity, rather than menstrual cycle pattern or follicle cohort size, determines hyperinsulinaemia, dyslipidaemia and hypertension in ageing women with polycystic ovary syndrome. Clin Endocrinol (Oxf) 55:767–776[CrossRef][Medline]
31. Gougeon A, Ecochard R, Thalabard JC 1994 Age-related changes of the population of human ovarian follicles: increase in the disappearance rate of non-growing and early-growing follicles in aging women. Biol Reprod 50:653–663[Abstract]
32. Block E 1952 Quantitative morphological investigations of the follicular system in women. Acta Anat 14:108–122[Medline]
33. Saxton DW, Farquhar CM, Rae T, Beard RW, Anderson MC, Wadsworth J 1990 Accuracy of ultrasound measurements of female pelvic organs. Br J Obstet Gynaecol 97:695–699[Medline]
34. Pavlik EJ, DePriest PD, Gallion HH, Ueland FR, Reedy MB, Kryscio RJ, van Nagell Jr JR 2000 Ovarian volume related to age. Gynecol Oncol 77:410–412[CrossRef][Medline]
35. Oppermann K, Fuchs SC, Spritzer PM 2003 Ovarian volume in pre- and perimenopausal women: a population-based study. Menopause 10:209–213[CrossRef][Medline]
36. Birdsall MA, Farquhar CM 1996 Polycystic ovaries in pre and post-menopausal women. Clin Endocrinol (Oxf) 44:269–276[CrossRef][Medline]
37. Carmina E, Chu MC, Longo RA, Rini GB, Lobo RA 2005 Phenotypic variation in hyperandrogenic women influences the findings of abnormal metabolic and cardiovascular risk parameters. J Clin Endocrinol Metab 90:2545–2549[Abstract/Free Full Text]
38. Carmina E, Rosato F, Janni A, Rizzo M, Longo RA 2006 Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 91:2–6[Abstract/Free Full Text]
39. Kiddy DS, Sharp PS, White DM, Scanlon MF, Mason HD, Bray CS, Polson DW, Reed MJ, Franks S 1990 Differences in clinical and endocrine features between obese and non-obese subjects with polycystic ovary syndrome: an analysis of 263 consecutive cases. Clin Endocrinol (Oxf) 32:213–220[Medline]
40. Pache TD, Wladimiroff JW, deJong FH, Hop WC, Fauser BCJM 1990 Growth patterns of nondominant ovarian follicles during the normal menstrual cycle. Fert Steril 54:638–642[Medline]

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