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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1191
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 11 4361-4368
Copyright © 2006 by The Endocrine Society

Defining Constant Versus Variable Phenotypic Features of Women with Polycystic Ovary Syndrome Using Different Ethnic Groups and Populations

C. K. Welt1, G. Arason1, J. A. Gudmundsson1, J. Adams, H. Palsdóttir, G. Gudlaugsdóttir, G. Ingadóttir and W. F. Crowley

Reproductive Endocrine Unit (C.K.W., J.A., W.F.C.), Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114; Þjónustumiidstöd Rannsóknaverkefna (H.P., G.G., G.I.), 105 Reykjavík, Iceland; and ARTmedica IVF Iceland (G.A.) and Department of Obstetrics and Gynecology (J.A.G.), Landspitali University Hospital, 101 Reykjavík, Iceland

Address all correspondence and requests for reprints to: Corrine 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: The phenotype of women with polycystic ovary syndrome (PCOS) is variable, depending on the ethnic background.

Objective: The phenotypes of women with PCOS in Iceland and Boston were compared.

Design: The study was observational with a parallel design.

Setting: Subjects were studied in an outpatient setting.

Patients: Women, aged 18–45 yr, with PCOS defined by hyperandrogenism and fewer than nine menses per year, were examined in Iceland (n = 105) and Boston (n = 262).

Intervention: PCOS subjects underwent a physical exam, fasting blood samples for androgens, gonadotropins, metabolic parameters, and a transvaginal ultrasound.

Main Outcome Measures: The phenotype of women with PCOS was compared between Caucasian women in Iceland and Boston and among Caucasian, African-American, Hispanic, and Asian women in Boston.

Results: Androstenedione (4.0 ± 1.3 vs. 3.5 ± 1.2 ng/ml; P < 0.01) was higher and testosterone (54.0 ± 25.7 vs. 66.2 ± 35.6 ng/dl; P < 0.01), LH (23.1 ± 15.8 vs. 27.6 ± 16.2 IU/liter; P < 0.05), and Ferriman Gallwey score were lower (7.1 ± 6.0 vs. 15.4 ± 8.5; P < 0.001) in Caucasian Icelandic compared with Boston women with PCOS. There were no differences in fasting blood glucose, insulin, or homeostasis model assessment in body mass index-matched Caucasian subjects from Iceland or Boston or in different ethnic groups in Boston. Polycystic ovary morphology was demonstrated in 93–100% of women with PCOS in all ethnic groups.

Conclusions: The data demonstrate differences in the reproductive features of PCOS without differences in glucose and insulin in body mass index-matched populations. These studies also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women. Finally, polycystic ovary morphology by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
POLYCYSTIC OVARY SYNDROME (PCOS) is diagnosed based on a constellation of signs and symptoms that have varied across time and between investigators. A strict definition of PCOS was suggested in a 1990 National Institutes of Health (NIH) conference and included hyperandrogenism, oligoovulation, and exclusion of other disorders manifesting similar clinical symptoms (1). Nevertheless, even subjects fitting these strict criteria can manifest differences in the associated features of PCOS based on differences in the severity of their hyperandrogenism, menstrual dysfunction, weight, and insulin resistance. Ethnicity also influences the variability of associated symptoms, both on a genetic and environmental basis. Cross-population studies are therefore necessary to ascertain key differences in phenotypes that may point to genetic variability or genetic or environmental modifiers of the PCOS phenotype in different ethnic groups.

Previous studies addressed the population differences by examining the phenotype of PCOS in women of different ethnic backgrounds. These investigations have had variable numbers and findings. Some have found marked differences in insulin resistance between subjects of different race or ethnicity (2, 3, 4, 5, 6, 7). Fewer studies have extensively examined ethnic variability in serum androgen and gonadotropin concentrations (2, 3, 4, 6, 7, 8), and only two have examined the ovaries on ultrasound (2, 6). Despite the paucity of these types of studies, they are critical for the ascertainment of universal criteria used for the diagnosis of PCOS.

To address the variability of PCOS across populations, the phenotypes of Caucasian women with PCOS in Iceland and Boston were examined. In addition, the phenotypes of Boston subjects with PCOS of Caucasian, African-American, Caucasian Hispanic, and Asian ancestry were compared simultaneously to determine ethnic variability. These studies: 1) examined a large number of PCOS subjects; 2) used a comprehensive and standardized phenotyping protocol; 3) cross-validated the interobserver variability; 4) used a single reference laboratory and a constant technique for assays throughout the study; 5) limited the number of observers; and 6) used two consistent readers of the ultrasounds. PCOS was diagnosed based on the 1990 NIH criteria (1) to ensure a severely affected phenotype that would presumably capture the metabolic and reproductive abnormalities known to accompany this syndrome (9). The data thus serve to compare the PCOS phenotype in a European and U.S. population in which the diagnostic criteria have tended to differ and also highlight the ethnic variability in PCOS in women living in the northeastern United States.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects fulfilling the NIH criteria for PCOS (1) in Iceland (n = 105) and Boston (n = 262), between the ages of 18 and 45 yr, were studied. Subjects in Iceland were identified from the private practices of two participating gynecologists (J.A.G. and G.A.; n = 59); a study on obesity if a screening questionnaire indicated irregular menstrual cycles, hirsutism, or acne (n = 16); a self-report of PCOS (n = 9), advertisements, family members of PCOS probands or for other reasons (n = 21). PCOS subjects in Boston were recruited by advertisements or from reproductive endocrine or primary care outpatient clinics. All PCOS subjects in Iceland were examined by one of two research nurses (H.P. and G.I.) trained by a Boston physician (C.K.W.), and all subjects in Boston were examined by a reproductive endocrinologist or a physician assistant. In addition, a group of control subjects was recruited in Iceland (n = 32) to provide normative data for Icelandic subjects with PCOS. The control subjects had regular menstrual cycles, 21–35 d and no reported or physical exam evidence of hyperandrogenism and were matched by age and body mass index (BMI) to PCOS subjects. Historic controls with regular menses and documented ovulation were used for the Boston population (10).

PCOS was defined as chronic oligomenorrhea (fewer than nine menstrual periods per year) and clinical and/or biochemical evidence of hyperandrogenism (1). Clinical hyperandrogenism was defined by one of the following features: 1) an elevated Ferriman Gallwey score or 2) acne on the face or back. An elevated Ferriman Gallwey score in Iceland was defined as greater than 6, the value used in a previous Scandinavian population and greater than the 95% confidence limit in the Icelandic control women (Table 1Go) (11). An elevated Ferriman Gallwey score in Boston was greater than 9, i.e. greater than the 95% confidence limit for the control population (10). Biochemical hyperandrogenism was defined as an androgen level greater than the 95% confidence limits in the Boston control population: 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) (10). Androgen levels in Icelandic control subjects were not used to identify the 95% confidence limits because they were drawn in the late follicular phase of the menstrual cycle. Late-onset congenital adrenal hyperplasia was excluded with a follicular phase 17-hydroxyprogesterone (17-OH progesterone) 3.0 ng/ml or less (9.1 nmol/liter) (12). All subjects had normal thyroid function and prolactin levels and a follicular phase FSH level in the premenopausal range. Subjects were on no hormonal medication, except for stable thyroid hormone replacement and did not have a progesterone level greater than 1 ng/ml (3.2 nmol/liter) as evidence of presumed recent ovulation.


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  		TABLE 1. Anthropomorphic features of the PCOS phenotype in Icelandic and Boston ethnic groups

 
Protocol

The study was approved by the Institutional Review Board of the Massachusetts General Hospital, the Data Protection Commission of Iceland, and the National Bioethics Committee of Iceland. All subjects gave their written informed consent.

All PCOS and Icelandic control subjects were studied 10 d or more after their last menstrual period to avoid the time frame in which LH and androgen levels are suppressed after a spontaneous ovulation (10). All subjects arrived after a 12-h fast and underwent a detailed history, physical exam, and tests including an assessment of hirsutism (13); measurement of waist circumference at the umbilicus and hip circumference at the widest diameter; a transvaginal or transabdominal ultrasound; and blood samples for lipid, glucose, insulin, gonadotropin, and sex-steroid levels. Subjects reported their ethnic background according to the categories recognized by the U.S. Public Health Service.

In addition to the fasting samples, blood samples were drawn at 10 and 20 min for LH and FSH to obtain an average gonadotropin concentration. Using data from blood samples collected every 10 min over 12 h in women with PCOS and ovulatory controls (10), we documented that the mean LH secretion from 12 h of frequent blood samples correlates well with the value obtained from the mean of the three samples collected from 0800–0820 h (r = 0.92, P < 0.01). Using these same data, the mean LH of three samples collected every 10 min for 20 min distinguishes PCOS subjects from their weight-matched controls (21.2 ± 13.0 vs. 6.6 ± 2.9, mean ± SD; P < 0.001; PCOS vs. controls, respectively). An oral glucose tolerance test was performed in the Boston subjects only, with blood sampling 2 h after a 75-g glucose load.

Subjects underwent a transvaginal ultrasound, or rarely a transabdominal ultrasound if the subject was not previously sexually active (ATL HDI 1500, 5 MHz convex array transducer; Philips, Bothell, WA), to assess ovarian morphology. Ultrasound scans were read and scored as polycystic ovarian (PCO) morphology, independently, by one of two experienced and blinded reviewers (C.K.W. or J.M.A.).

Validation of Ferriman Gallwey scoring

The variability of the Ferriman Gallwey scoring between the two study sites was also assessed (13). Two different observers scored hirsutism in a subset of Icelandic subjects (H.P. or G.I. from Iceland and C.K.W. from Boston; n = 50), independently, at the time of the subject’s visit.

Hormonal assays

Serum LH and FSH were measured by the Reproductive Endocrine Unit’s reference laboratory using a two-site monoclonal nonisotopic system (Axsym; Abbott Laboratories, Abbott Park, IL) (14). 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) (15). 17-OH progesterone was measured by RIA (16). SHBG was measured using a chemiluminescent enzyme immunometric assay (Immulite; Diagnostic Products Corp.) (15). Insulin was measured using an immunochemiluminescent immunoassay (Immulite 2000; Diagnostic Products Corp.), with a lower limit of detection of 2.0 µIU/ml (14.4 pmol/liter).

Data analysis

Ovarian volume was calculated as length x width x height in centimeters multiplied by 0.5233, i.e. the formula for an ellipse (17). PCO morphology was defined as at least one ovary with 10 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 (18, 19, 20). The maximum ovarian volume and follicle number in both ovaries was used for analysis, excluding the volume of an ovary with a dominant follicle, corpus luteum, or cyst.

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

Data were log normalized and compared between Boston and Icelandic Caucasian PCOS subjects and between Icelandic control and PCOS subjects using t tests. A subset analysis was performed for any variable manifesting a significant interaction between BMI (<30 or ≥ 30 kg/m2) and group. Data were compared between ethnic groups in Boston using one-way ANOVA on ranks and analysis of covariance to control for differences in age, weight, and BMI. A {chi}2 test was used to compare categorical data. Spearman correlations were used to evaluate associations. The data are reported as mean ± SD except where noted. P < 0.05 was taken as the minimum level of significance, except for correlations in which P < 0.003 was used to account for multiple comparisons.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Anthropomorphic features of the PCOS phenotype across populations

PCOS subjects in Boston self-reported their race as Caucasian/non-Hispanic (n = 172, 65.6%), African-American (n = 44, 16.9%), Hispanic (n = 25, 9.5%), and Asian (n = 21, 8.0%). All Icelandic subjects reported their race as Caucasian. Therefore, Icelandic subjects were compared with the Caucasian PCOS population in Boston. Boston subjects from different ethnic groups were compared in a secondary analysis.

Icelandic women with PCOS were similar in age to the Boston subjects (Table 1Go). Although Icelandic subjects weighed more than Boston PCOS subjects, they were also taller and their BMIs did not differ (Table 1Go). The height of Icelandic women with PCOS was similar to that measured in Icelandic controls and in recent studies of adult women in Iceland [mean ± SD, 1.67 ± 0.05 and 1.68 ± 0.06 m (23, 24)]. Although waist circumferences in both populations were similar, the hip circumference of the Icelandic subjects was greater and their waist to hip ratio was smaller.

The systolic blood pressures of Icelandic PCOS subjects were higher as was the percentage of PCOS subjects with an elevated systolic blood pressure of 130 mm Hg or greater (34.4 vs. 22.4%; P < 0.05; Iceland vs. Boston, respectively). However, the diastolic blood pressure did not differ. The Ferriman Gallwey scores assigned during independent assessment of 50 Icelandic PCOS subjects were similar between the research nurses in Iceland and the physician in Boston (6.2 ± 4.6 vs. 6.0 ± 3.9; H.P./G.I. vs. C.K.W., respectively, P = 0.9). Therefore, the scores can be directly compared in the two groups. The Ferriman Gallwey scores and the percentages of subjects with an elevated Ferriman Gallwey score, acne, and acanthosis were lower in Icelandic PCOS subjects than their Boston counterparts. The Ferriman Gallwey scores and percentages of subjects with an elevated Ferriman Gallwey score and acanthosis in Icelandic controls were even lower than in Icelandic PCOS subjects.

Within the Boston PCOS cohort, age, weight, height, BMI, and waist and hip circumference were significantly different among the different ethnic groups. African-American PCOS subjects had a greater weight, BMI, and waist and hip circumference than Caucasian and Asian subjects (Table 1Go and Fig. 1Go). Caucasian women were taller than Asian women. There were no differences in the waist to hip ratios, systolic and diastolic blood pressures, Ferriman Gallwey scores, or the proportion of subjects affected by acne or acanthosis between groups.


Figure 1
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  		FIG. 1. BMI, waist circumference, and fasting insulin (Ins) in Boston women with PCOS from different ethnic backgrounds: Caucasian (Cauc), African-American (Af Am), Hispanic (Hisp), and Asian. Data are shown in box and whisker plots. The box represents the 25 and 75% confidence limits, and the internal line represents the median. Bars indicate the SE, and black dots indicate the 5 and 95% confidence limits. There is a statistically significant difference in median values among treatment groups for BMI, waist circumference, and fasting insulin (all P < 0.01); however, the differences in waist circumference and fasting insulin are accounted for by BMI. Differences in pairwise multiple comparisons using Dunn’s method are indicated (*, P < 0.05). To convert to SI units, multiply insulin by 7.175.

 
Reproductive abnormalities of PCOS across populations

LH levels and LH:FSH ratios were lower in Icelandic compared with Boston subjects with PCOS (Table 2Go). In addition, androstenedione levels and the androstenedione to testosterone ratio were higher, and testosterone, free testosterone, and DHEAS concentrations were lower in Icelandic, compared with Boston subjects with PCOS (Table 2Go and Fig. 2Go). There was a significant interaction between group and BMI (<30 or ≥ 30 kg/m2) for androstenedione. In women with PCOS and a BMI less than 30 kg/m2, androstenedione was similar in Iceland and Boston (3.7 ± 1.3 vs. 3.6 ± 1.1 ng/ml; P = 0.7), whereas in women with a BMI of 30 kg/m2 or greater, androstenedione was higher in Iceland than Boston (4.2 ± 1.2 vs. 3.5 ± 1.3 ng/ml; P < 0.001). Gonadotropin and androgen levels were higher in Icelandic PCOS, compared with control subjects. LH correlated with androstenedione (r = 0.366; P < 0.001) and testosterone (r = 0.264; P < 0.001) in all Boston subjects grouped together and Icelandic subjects (r = 0.273; P < 0.01 and r = 0.352; both P < 0.001).


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  		TABLE 2. Reproductive features of the PCOS phenotype in Icelandic and Boston ethnic groups

 

Figure 2
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  		FIG. 2. Testosterone (T), androstenedione (AD), and AD to T ratio in Caucasian women with PCOS from Boston and Iceland. Data are shown in box and whisker plots. The box represents the 25 and 75% confidence limits and the line represents the median. Bars indicate the SE and black dots indicate the 5 and 95% confidence limits. To convert to SI units, multiply testosterone by 0.04467 and androstenedione by 3.492. *, P < 0.05.

 
In contrast to differences between Caucasian Icelandic and Boston PCOS subjects, there were no differences in the gonadotropins or sex steroids between the Boston ethnic groups, with the exception of calculated free testosterone and SHBG levels. In the Boston subjects with PCOS, BMI and insulin correlated highly with SHBG (r = –0.60 and r = –0.5, BMI, and insulin, respectively; both P < 0.001) and free testosterone (r = 0.43 and r = 0.35; both P < 0.001), and the differences in SHBG and free testosterone between ethnic groups were accounted for by differences in BMI and insulin levels, with no independent effect of ethnicity.

Metabolic features of the PCOS phenotype across populations

No differences in glucose, insulin, or HOMA were found in the Caucasian Icelandic and Boston women with PCOS (Table 3Go). There were no differences in cholesterol, low-density lipoprotein (LDL) or triglycerides between groups. However, high-density lipoprotein (HDL) levels were lower in Icelandic compared with Boston subjects with PCOS and there were more Icelandic subjects with HDL less than 50 mg/dl [1.3 mmol/liter; Table 3Go (25)]. There were no differences in the prevalence of impaired fasting glucose, type 2 diabetes, or metabolic syndrome in the two groups (Table 3Go). There was a significant interaction between group and BMI (<30 or ≥ 30 kg/m2) for total cholesterol and LDL. In women with PCOS and a BMI less than 30 kg/m2, cholesterol was similar (182.8 ± 37.9 vs. 175.0 ± 33.2 mg/dl; P = 0.3), and LDL was higher (114.7 ± 31.9 vs. 100.6 ± 30.0 mg/dl; P = 0.01) in Iceland than Boston. In contrast, in women with a BMI of 30 kg/m2 or greater, cholesterol tended to be lower (182.2 ± 32.5 vs. 194.5 ± 37.3 mg/dl; P = 0.07), whereas LDL was similar in Iceland and Boston (113.7 ± 27.9 vs. 121.3 ± 31.1 mg/dl; P < 0.01).


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  		TABLE 3. Metabolic features of the PCOS phenotype in Icelandic and Boston ethnic groups

 
Insulin correlated directly with testosterone (r = 0.261; P < 0.01) and inversely with SHBG in Icelandic subjects (r = –0.493; P < 0.001). No relationship between insulin and testosterone was apparent in Boston subjects and SHBG results are reported above.

Insulin and HOMA differed between Boston ethnic groups with higher insulin levels and HOMA in African-American compared with Asian and Caucasian women (Table 3Go and Fig. 1Go). Both insulin (r = 0.68; P < 0.001) and HOMA (r = 0.68; P < 0.001) correlated with BMI, and the difference in insulin and HOMA between groups was entirely accounted for by BMI. Fasting glucose, cholesterol, and triglyceride levels did not differ between groups. Considering either the fasting glucose or the oral glucose tolerance test results (Boston subjects only), there was no difference in the proportion of impaired fasting glucose or impaired glucose tolerance in the ethnic groups, but there was more type 2 diabetes among African-Americans with PCOS. There was no difference in the prevalence of metabolic syndrome between groups. However, when the components of metabolic syndrome were compared separately, the waist circumference was increased in a greater number of African-American women and triglycerides were increased in a greater number of Asian women, compared with the other ethnic groups (Table 3Go).

Ovarian morphology by ultrasound across populations

Maximum ovarian volumes and the number of follicles observed in a single plane on ultrasound were smaller in Icelandic than Boston subjects with PCOS (Table 4Go) and were even smaller in Icelandic control than Icelandic PCOS subjects. There was no difference in the proportion of ovaries, more than 90% in the Icelandic and Boston PCOS groups, meeting the criteria for PCO morphology (18, 19, 20). However, there were more normal ovaries in the Icelandic group when compared with Boston group. There were more indeterminate ultrasounds in the Icelandic PCOS group because additional views were needed to define PCO morphology in some cases.


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  		TABLE 4. Ovarian morphology on ultrasound in Icelandic and Boston women with PCOS from different ethnic groups

 
In Boston PCOS subjects, ovarian volume correlated with testosterone (r = 0.357; P < 0.001) and androstenedione (r = 0.234; P = 0.001) but not insulin or LH levels. In the Icelandic subjects, there was no correlation between ovarian volume and testosterone, androstenedione, insulin, or LH. In both Icelandic and Boston PCOS subjects, maximum follicle number in a single plane correlated with testosterone (r = 0.300 and r = 0.390; both P < 0.001, respectively) and androstenedione (r = 0.463 and r = 0.318; both P < 0.001).

Ovarian volume and follicle number differed among the ethnic subgroups. Ovarian volume and follicle number were higher in African-American than Asian women and follicle number was higher in Caucasian than Asian women with PCOS in Boston. These differences were not accounted for by age or BMI. As in the Caucasian group, the majority of ultrasounds in the ethnic subgroups demonstrated PCO morphology.

Definitional considerations

Twenty-four percent of Icelandic subjects and 16% of Boston subjects had hyperandrogenism on the basis of acne, alone. Because acne is not uniformly considered a sign of hyperandrogenism in studies of PCOS, these subjects were removed in a separate analysis. There was no longer a difference in waist to hip ratio (0.88± 0.08 vs. 0.90± 0.08; P = 0.1), LH (25.2± 17.5 vs. 27.7± 16.4 IU/liter; P = 0.2), and LH to FSH ratio (2.5± 1.6 vs. 2.7± 1.5 IU/liter; P = 0.1) between Icelandic and Boston subjects when subjects with acne only were removed. The 17-OH progesterone was higher in Icelandic than Boston subjects (1.55± 0.68 vs. 1.33± 0.58 ng/ml; P < 0.05). The results of other analyses did not change.


   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In an era when genetics is increasingly defining the etiology of complex diseases (26), careful phenotypic examination of large cohorts from different ethnic and population backgrounds is important. Given that PCOS fits the general criteria of a polygenic disorder and has a clear-cut genetic component (27), comparing the phenotype of PCOS across countries and ethnic groups using consistent phenotyping techniques, observers, and diagnostic criteria was the goal of this study. Caucasian women with PCOS in Boston were compared with their Icelandic counterparts and among various Boston ethnic subsets using the 1990 NIH definition to weight the study for a severely affected phenotype (1). This comparison demonstrates several interesting similarities and differences between these groups, most remarkably the higher androstenedione and lower testosterone in Icelandic subjects, compared with Caucasian Boston subjects. LH is also lower in Icelandic women with PCOS, compared with Boston women, as are the ovarian volumes and follicle numbers. However, there was no difference in fasting glucose and insulin levels. In addition, as was anticipated by previous Scandinavian studies (11), Icelandic women with PCOS and controls had lower Ferriman Gallwey scores. In contrast, there were no differences in sex steroid and gonadotropin levels among the different ethnic groups in Boston. Although insulin and HOMA were higher in the African-American subgroup in Boston, these differences could be accounted for by BMI. These findings suggest that there are subtle differences in the reproductive aspects of the PCOS phenotype in Caucasian Icelandic and Boston subjects with PCOS, whereas differences in insulin dynamics are related to differences in BMI and not country of origin or ethnic background in this data set.

The higher LH, testosterone, and DHEAS levels in the Boston cohort contrasted with the higher androstenedione and androstenedione to T ratio observed in the Icelandic cohort. These striking reproductive differences have not been previously reported across populations (2, 3, 4, 6, 7, 8) and were not evident in ethnic subgroups in Boston. Although one small study found that Japanese women had lower Ferriman Gallwey scores and serum 3{alpha}-androstanediol glucuronide concentrations than Hispanic U.S. and Italian subjects (2), the majority of previous studies recruited patients based on an elevated serum androgen level; testosterone, free testosterone, dehydroepiandrosterone, and/or androstenedione, possibly decreasing the ability to resolve subtle androgen differences (2, 3, 4, 6, 7, 8). One study also performed laboratory testing after a spontaneous or progesterone-induced withdrawal bleed (2), an intervention known to suppress LH and androgens (10). Because androstenedione is a much less potent androgen than testosterone and must be converted to testosterone and 5{alpha}-dihydrotestosterone to exert its maximal action (28), it is possible that the predominance of androstenedione resulted in the lower Ferriman Gallwey scores and prevalence of acne in Icelandic subjects.

There are several possible explanations for the higher androstenedione and lower testosterone levels in Icelandic PCOS women. The lower DHEAS levels argue against greater adrenal androgen production in Icelandic women with PCOS. The predominance of higher androstenedione in Icelandic women with a BMI of 30 kg/m2 or greater suggests that the androstenedione differences may be driven by a factor related to weight. Alternatively, there may be an intrinsic difference in the 17ß-hydroxysteroid dehydrogenase pathway in women from Iceland and Boston. Indeed, a polymorphism in the promoter region of the type 5, 17ß-hydroxysteroid dehydrogenase enzyme found in one woman with severe PCOS has been associated with increased activity of this enzyme and formation of more testosterone in vitro (29). It is unknown whether this or other polymorphisms affecting the activity of this enzyme pathway are more common in the Boston population.

These population differences in androstenedione and testosterone concentrations in Boston and Iceland have potential clinical and research implications. It has been suggested that testosterone is the most sensitive androgen measurement in women with PCOS; therefore, it is often measured alone when conducting clinical research studies (30). Measurement of androstenedione was not recommended routinely based on the paucity of normative data (19). Nevertheless, in the Icelandic women with PCOS who had an elevated androgen level, 31 (30%) had an elevated androstenedione alone and would have been excluded from participation if an elevated testosterone had been required. Thus, whereas testosterone appears to be an adequate marker of hyperandrogenism for PCOS subjects in the northeastern United States, androstenedione is also required as a marker of hyperandrogenism in Iceland and possibly other populations that have a low levels of hirsutism (2).

In contrast to differences in the reproductive phenotype, fasting insulin and glucose measurements were identical in Caucasian Icelandic and Boston subjects with PCOS. Furthermore, differences in insulin and HOMA in the ethnic subgroups in Boston were accounted for by differences in weight and BMI. Insulin parameters in women with PCOS have been compared previously in different ethnic groups (2, 3, 4, 5, 6, 7, 8). These studies have found higher fasting insulin and hemoglobin A1C and increased insulin resistance in black, Caribbean Hispanic, Mexican, and Asian women, compared with Caucasian women, and Hispanic U.S. and Italian women, compared with Japanese women with PCOS (2, 3, 4, 5, 6, 7, 8). As in the current study, the more insulin resistant groups had a higher BMI in some previous studies (2, 7), although Hispanic and African-Americans have greater insulin resistance than Caucasians in hyperinsulinemic clamp studies (31, 32). Differences in insulin concentrations may have exacerbated the elevated free testosterone levels in African-American and Hispanic women in Boston in whom BMI was highest.

From a cardiovascular perspective, Icelandic subjects had higher systolic blood pressures and lower HDL concentrations than Boston women with PCOS, perhaps pointing to another unique genetic or environmental component in Iceland. Despite these unfavorable metabolic parameters in Icelandic subjects, there was no difference in the proportion of subjects with metabolic syndrome in the two groups, nor was there a difference among the ethnic subgroups in Boston. Of note, the prevalence of metabolic syndrome in all PCOS subjects in the current study was lower than the 33–46% prevalence reported in four recent studies (33, 34, 35, 36) but higher than that in two smaller studies (37, 38). The percentage of subjects with BMI greater than 30 kg/m2 (34, 36) and the mean BMI (33, 35) of subjects with metabolic syndrome was much greater in studies demonstrating a higher prevalence, and the BMI was lower in studies manifesting a lower prevalence of metabolic syndrome than the current study (37, 38). Thus, it appears that weight and its metabolic consequences have a major impact on the prevalence of metabolic syndrome in PCOS populations, and there may be little risk for metabolic syndrome in PCOS subjects independent of the obesity that often accompanies it.

The majority of PCOS subjects in the current study met the ultrasonographic criteria for PCO morphology originally identified by Adams et al. (18), in combination with an ovarian volume greater than 10 cc. The proportion of PCOS subjects with PCO morphology on ultrasound was similar to that demonstrated by others using the same ultrasound morphology criteria (39, 40). Although the specificity of PCO morphology documented by ultrasound is greater when designating the threshold follicle count at 12 follicles of 2–9 mm (sensitivity 75%; specificity 99%) (20), using a threshold of 10 follicles (18) has an increased sensitivity and adequate specificity (86 and 90%, respectively). This increased sensitivity was necessary to evaluate the Iceland ultrasound scans because a limited number of pictures were available. These data demonstrate that the PCO morphology is a consistent feature in women with PCOS when identified by irregular menses and hyperandrogenism, regardless of the country of origin.

Our results also demonstrate that ovarian volume and follicle number were higher in Boston, compared with Icelandic subjects with PCOS, possibly in line with their elevated LH levels. The higher ovarian volumes and follicle numbers correlated with the higher serum testosterone and androstenedione in the current and previous studies (41, 42). These data suggest that follicle number on ultrasound and related ovarian volume are anatomical manifestations that parallel the hyperandrogenic milieu of women with PCOS.

The strength of the current study is the large number of Caucasian subjects, compared in Iceland and Boston. The limitation is the small number in the different ethnic subsets in Boston, although the numbers were similar to or greater than those in the majority previous studies (2, 3, 4, 7, 8). Of note, the reproductive and ovarian data from the Boston ethnic subsets was analyzed concurrently and using the same methods as in the Caucasian subjects. Therefore, the small numbers notwithstanding, an absence of reproductive hormone differences in the Boston ethnic subgroups provides a remarkable contrast to the differences in the two Caucasian populations and highlights their potential importance.

Examining PCOS subjects from Boston and Iceland and different ethnic groups thus demonstrates differences in the reproductive features without differences in the insulin parameters in BMI-matched populations. The data also suggest that measuring androstenedione is important for the documentation of hyperandrogenism in Icelandic women and that the Ferriman Gallwey score is variable in hyperandrogenic populations. They further suggest that polycystic ovary morphology assessed by ultrasound is an almost universal finding in women with PCOS as defined by hyperandrogenism and irregular menses.


   Acknowledgments
 
We thank Patrick Sluss, Ph.D., and Joseph Moy for their assay expertise. We also thank Kristleifur Kristjansson, M.D., Struan Grant, Ph.D., Larus Gudmundsson, and Gyda Bjornsdottir for their expert assistance with the study design, data management, and retrieval.


   Footnotes
 
This work was supported by 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: The authors have nothing to disclose.

First Published Online August 29, 2006

1 C.K.W., G.A., and J.A.G. contributed equally to the work. Back

Abbreviations: BMI, Body mass index; DHEAS, dehydroepiandrosterone sulfate; HDL, high-density lipoprotein; HOMA, homeostasis model assessment; LDL, low-density lipoprotein; 17-OH progesterone, 17-hydroxyprogesterone; PCO, polycystic ovarian; PCOS, polycystic ovary syndrome.

Received June 1, 2006.

Accepted August 21, 2006.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
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