Polycystic Ovarian Syndrome in Taiwanese Women

©2010 Taipei Medical University

R E V I E W A R T I C L E

1. Introduction

Polycystic ovary syndrome (PCOS), which is an extremely common disorder in women of reproductive age, is a heterogeneous collection of signs and symptoms that,

gathered together, form a spectrum of a disorder. In-vestigating PCOS is crucial as it is now considered to increase metabolic and cardiovascular risk, thereby im-pacting the health of women to a much greater extent than previously thought. Diagnosis of PCOS is principally

Polycystic ovary syndrome (PCOS) is an extremely common disorder in women of reproduc-tive age. Diagnosis of PCOS is principally based on clinical and physical findings. Diagnostic criteria and PCOS definitions used by clinicians and researchers are almost as heterogene-ous as the syndrome. Of those diagnosed with PCOS using the 2003 Rotterdam criteria, 61% fulfilled the 1990 National Institutes of Health criteria for unexplained hyperandro-genic chronic anovulation. Patient populations with the new phenotypes have less severe ovulatory dysfunction and less androgen excess than patients diagnosed using the 1990 National Institutes of Health criteria. These findings might be common across all female populations with PCOS, in Asian or Western countries. Data for clinical hyperandrogenism indicates that the prevalence of hirsutism in Taiwanese PCOS women is lower than that for Caucasian/Western women. The extent of metabolic abnormalities in women with PCOS may vary with phenotype, age and ethnicity. Obesity represents a major risk factor for met-abolic syndrome and insulin resistance. Approximately 40–50% of all women with PCOS are overweight or obese. Obese subjects with PCOS have a higher risk of developing oligomen-orrhea, amenorrhea and biochemical hyperandrogenemia than non-obese women with PCOS. Moreover, obese women with PCOS have significantly more severe insulin resis-tance, lower serum luteinizing hormone levels, and lower luteinizing hormone to follicle-stimulating hormone ratios than those of non-obese women with PCOS. PCOS women in Taiwan have a higher luteinizing hormone to follicle-stimulating hormone ratio and lower insulin resistance than those in PCOS women in Western countries. However, the average body mass index is significantly lower in Taiwanese PCOS women than in Western women, which might partially explain the difference between these two populations in terms of clin-ical and biochemclin-ical presentations. To further document the ethnic variation between women with PCOS in Taiwan and Western countries, future studies should pay attention to the effect of obesity on the diagnosis and clinical presentations of PCOS-related syndromes. Received: Mar 10, 2010 Revised: Jun 13, 2010 Accepted: Jul 13, 2010 KEY WORDS: hyperandrogenism; obesity; phenotypes;

polycystic ovary syndrome; Taiwan

Polycystic Ovarian Syndrome in Taiwanese Women

So-Jung Liang

, Szu-Yuan Chou

, Giueng-Chueng Wang

, Chii-Ruey Tzeng

,

Chun-Sen Hsu

, Ming-I Hsu

*

1_{Department of Obstetrics and Gynecology, Taipei Medical University, Wan-Fang Hospital, Taipei, Taiwan} 2_{Department of Laboratory Medicine, Taipei Medical University, Taipei, Taiwan}

3_{Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan}

*Corresponding author. Department of Obstetrics and Gynecology, Taipei Medical University, Wan Fang Hospital, 111 Hsing-Lung Road, Section 3, Taipei 116, Taiwan.

based on clinical and physical findings. The first compre-hensive definition arose from a conference sponsored by the National Institutes of Health–National Institute for Child and Human Development (NIH-NICHD) in April 1990.1 The recommended NIH diagnostic criteria are as follows: clinical or biochemical evidence of hy-perandrogenism, chronic anovulation and exclusion of other known disorders. However, most gynecologists are more likely to use morphological analysis of ovaries by ultrasonography to facilitate the diagnosis in clinical practice. Therefore, redefining PCOS to incorporate an appropriate definition of a polycystic ovary is required.2 In 2003, new guidelines for diagnosing PCOS were sug-gested at a joint meeting of the European Society for Human Reproduction and the American Society of Reproductive Medicine. A diagnosis of PCOS can be reached when at least two of three criteria are met: hy-perandrogenism and/or hyperandrogenemia (HA); oli-gomenorrhea or amenorrhea, or anovulation (oligo-an); polycystic ovary morphology (PCOM); and the exclusion of any androgen excess disorders.3 The Rotterdam 2003 criteria have expanded rather than replaced the 1990 NIH criteria. These new diagnostic criteria have added the following two PCOM phenotypes:1 (1) PCOM with HA and without oligo-an;2 and (2) PCOM with oligo-an and without HA.4 However, The Androgen Excess and PCOS Society recently suggested that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-an and/ or polycystic ovaries), and the exclusion of related dis-orders.5 The prevalence of PCOM in women of repro-ductive age has been reported to be 22–33%.2,6 PCOS diagnosed using the 1990 NIH criteria occurs in roughly 6–8% of women of reproductive age.7 The prevalence and clinical manifestations of PCOS should be reevalu-ated after applying these new diagnostic criteria. More-over, ethnic differences in clinical presentations of PCOS have been demonstrated in several studies.8–11

According to the three diagnostic criteria for PCOS, all women can be classified into three subgroups: (1) healthy women who have a normal ovary appearance, do not have oligomenorrhea or amenorrhea, and have no clinical or biochemical presentations of androgen excess; (2) PCOS risk factor-positive (PCOS-rf ) women who have only one of three PCOS components: (i) PCOM only, (ii) oligo-an only, and (iii) HA only; (3) PCOS women who present with at least two of the following criteria: (i) PCOM, (ii) oligo-an, or (iii) HA (Figure 1).3

Both healthy control and PCOS-rf groups belong to the group of non-PCOS subjects. Our previous study showed that disturbances caused by several clinical pres-entations in PCOS-rf women were less severe than in women with PCOS but were still significantly different from those in healthy control women.12

Using the Rotterdam 2003 criteria, four PCOS pheno-types can be classified as NIH subgroups and non-NIH subgroups as follows.

A. NIH subgroup

1. (HA + oligo-an type): hyperandrogenism and/ or hyperandrogenemia and oligomenorrhea/ amenorrhea without polycystic ovary morphol-ogy; this phenotype is PCOS without PCOM. 2. (HA + oligo-an + PCOM type): hyperandrogenism

and/or hyperandrogenemia and oligomenorrhea/ amenorrhea with polycystic ovary morphology; this phenotype is PCOS with all three diagnostic components.

B. Non-NIH subgroup

3. (HA + PCOM type): hyperandrogenism and/or hyperandrogenemia and polycystic ovary mor-phology without oligomenorrhea/amenorrhea; this phenotype is PCOS without oligo-an. 4. (Oligo-an + PCOM type):

oligomenorrhea/amen-orrhea and polycystic ovary morphology without hyperandrogenism and/or hyperandrogenemia; this phenotype is PCOS without HA.

Compared with the NIH 1990 criteria, polycystic ovary morphology is a new diagnostic criterion. In a study of Taiwanese women using the 2003 Rotterdam criteria, our results showed that of those women diagnosed with PCOS, 61% fulfilled the 1990 NIH criteria for un-explained hyperandrogenic chronic anovulation.8 The percentages of patients with the two newly extended phenotypes were as follows: 18% had PCOS without HA and 21% had PCOS without oligo-an.8 However, the patient populations with the new phenotypes had less severe ovulatory dysfunction and less androgen excess than patients diagnosed using the 1990 NIH criteria. The prevalence of PCOM has been suggested to be higher than 20% in both Asian and Western women.13,14 PCOM is the most common PCOS component in patients; 91% of patients diagnosed with the Rotterdam criteria and 85% diagnosed with the NIH criteria have PCOM.

PCOM

Ovulatory dysfunction Androgen

excess

Figure 1 Diagnostic criteria and phenotypes of polycystic ovary syndrome.

For clinical presentations, excess androgen has a princi-pal role in diagnostic criteria. It has been demonstrated that PCOS without excess androgen comprises one of the least severe phenotypes.5,8 Chae et al’s study of Korean women found that PCOS without HA is a com-mon phenotype in Korea and these women are less likely to have metabolic dysfunction, insulin resistance and elevated blood pressure.9 Our study and previous reports support the proposal that excess androgen is the condition directly responsible for the signs and symptoms that are recognized as PCOS.5,8,9 Therefore, we can summarize the severity in clinical and biochem-ical syndromes of PCOS-related disturbances in women using various inclusion criteria as shown in Figure 2.

2. Clinical Presentation of

Hyperandrogenism in Taiwanese

Women With PCOS

The most apparent signs of androgen excess are exter-nal manifestations, including oily skin, acne, hirsutism, android obesity, and androgenic alopecia. Hirsutism is not only a function of circulating androgen levels, it can also be determined by genetic factors. Only 28–35% of Asian women with PCOS have hirsutism.8,15 DeUgarte et al applied the 1990 NIH diagnostic criteria to investigate 271 PCOS patients with average modified Ferriman- Gallwey (mF-G) scores of 8.0 and determined that 77%

had hirsutism.16 We utilized the same criteria (NIH diag-nostic criteria) and a similar scoring system to evaluate 95 Taiwanese women, and found that 35% had hir-sutism and average mF-G scores of 4.4. Although 53% of PCOS patients under the Rotterdam 2003 criteria have excess clinical androgen, the incidence of hir-sutism (28%) was less than that for acne (35%) in our study of Taiwanese women.8

To study and document the clinical presentation of hyperandrogenism in Taiwanese women, we recently reported a study of 627 women in the outpatient clinic of Wan-Fang Hospital.17 Of the 627 women studied, 55% (346/627) had PCOS, 33% (210/627) had hyperandro-genemia, 38% (240/627) had acne, 19% (121/627) had hirsutism, and 34% (213/627) were obese. Our survey showed that women suffering from obesity had a higher incidence of PCOS (64% vs. 51%) and hyperandrogen-emia (51% vs. 25%), a lower incidence of acne (31% vs. 42%), and a higher serum total testosterone than non-obese subjects. Even though non-obese women had signi-ficantly higher serum total testosterone levels, they still had a lower incidence of acne than non-obese women, and this was found uniformly in PCOS, non-PCOS, and hyperandrogenemic and non-hyperandrogenemic subjects.17

The effect of hyperandrogenemia on cutaneous mani-festations, e.g., acne, might be alleviated by obesity. This phenomenon could be explained by aromatase activity in adipose tissue. The increase in adipose tissue

Reproductive age women

PCOS risk factor (+)

Rotterdam 2003 criteria

Androgen excess society criteria

NIH 1990

Figure 2 Diagram of the severity in clinical and biochemical syndromes of polycystic ovary syndrome-related disturbance in women using various inclusion criteria.

is associated with an increase in the enzyme aromatase.18 Aromatase converts testosterone to estradiol, and is lo-calized to sebaceous glands and to both outer as well as inner root sheath cells of anagen terminal hair folli-cles. Aromatase may play a “detoxifying” role by remov-ing excess androgens.19 Estrogens may act by several mechanisms that negatively influence sebaceous gland growth or lipid production.20 Therefore, obese women might present with fewer clinical manifestations of hy-perandrogenism than non-obese women.

3. Inappropriate Gonadotropin Secretion

in Taiwanese Women With PCOS

Inappropriate gonadotropin secretion, especially in-creased mean luteinizing hormone (LH) levels, is a very common finding in women with PCOS.21 Although LH levels and the LH to follicle-stimulating hormone (FSH) ratio are not required for diagnosis in Rotterdam crite-ria,1 they are still major criteria in the diagnosis of PCOS in Japanese women. Disturbance of the hypothalamic-pituitary-ovarian axis is still thought to have a key etio-logic role in PCOS patients.22

To evaluate the predictive value of PCOS diagnostic criteria, we performed a receiver operating character-istic (ROC) curve analysis and showed that the area under the ROC curve for the LH to FSH ratio is similar to the areas under the ROC curve for total testosterone and for average ovarian volume.12 Because total testo-sterone serum levels and average ovarian volume are both used as inclusion criteria for PCOS diagnosis, the LH to FSH ratio might be a useful marker of PCOS in Taiwanese women.12 We further evaluated the role of the LH to FSH ratio in patients with oligomenorrhea or anovulation by using ROC analysis. For the diagnosis of oligomenorrhea or anovulation, the LH to FSH ratio ap-pears to have better prediction power than total testo-sterone and average ovarian volume.12

To set the threshold of the LH to FSH ratio for iden-tifying women with PCOS, poor sensitivity is the most critical component in diagnosis.23 Our results showed a sensitivity of 13% and specificity of 96% at an LH-FSH ratio of > 3, and 35% and 90%, respectively, at a ratio of > 2.12 _{The decision thresholds of the LH to FSH ratio in} PCOS diagnosis shows that an LH to FSH ratio of > 1 re-sults in the best combination of sensitivity (69%) and specificity (80%).12 Therefore, we propose that the thresh-old LH to FSH ratio could be set as > 1 for the best com-bination of sensitivity and specificity for the diagnosis of both PCOS and oligomenorrhea or amenorrhea.

4. PCOM in East Asian Women With PCOS

Classically, PCOM has been described as enlarged ova-ries containing numerous peripheral antral follicles with

increased ovarian volume. The ultrasound appearance of PCOM has been recently codified as ≥ 12 follicles in either ovary measuring 2–9 mm in diameter, and/or increased ovarian volume of > 7 mL.24 However, Chen et al studied 432 Chinese women with PCOS using NIH criteria and compared them with 153 age-matched women as controls, and found that the thresholds for PCOS were 6.4 cm3 for mean ovarian volume and 10 for mean follicle number.25 Both mean ovarian volume and mean follicle number of Asians might be different compared with Western PCOS women.25 Women with PCOM only have a significantly lower ovarian volume, serum LH, testosterone and dehydroepiandrosterone sulfate levels but higher serum sex hormone-binding globulin levels compared with PCOS women; PCOM only represents a milder end of the PCOS spectrum.26 Chen et al’s study in Taiwanese women reported that the number of antral follicles and ovarian volume showed a significant correlation with anti-mullerian hormone, total testosterone and the free androgen index; and anti-mullerian hormone, body mass index (BMI) and total testosterone were independently related to the number of antral follicles.27

5. Insulin Resistance and Glucose

Intolerance in Taiwanese Women

With PCOS

Shi et al reported that 1040 Chinese women with PCOS had an impaired glucose tolerance (IGT) prevalence of 17.2% and a type 2 diabetes prevalence of 16.6%.28 Chen et al evaluated 102 PCOS patients and reported that the prevalence of IGT was 20.5% and that of non-insulin-dependent diabetes mellitus was 1.9%.29 Lee et al reported that in Korean women with PCOS, the prev-alence of IGT was 17.0% and the prevprev-alence of type 2 diabetes was 1.0%.30 Wei et al reported 356 Taiwanese with PCOS and 974 control infertility patients and found that the prevalence of IGT was 7.6% and diabe-tes mellitus was 3.1% in patients with PCOS compared with 2.9% and 0.2% in the control group, respectively.31 Legro et al studied 254 women with PCOS and found that the IGT prevalence was 31.1% and the type 2 dia-betes prevalence was 7.5%.32 Chinese PCOS women have a lower prevalence of IGT than American PCOS women.28,29,31,32 Cheung et al reported that the preva-lence of metabolic syndrome in Hong Kong Chinese women with PCOS increased from 16.7% at under 30 years of age to 53.3% at over 40 years.33 Women with PCOS have a fivefold increase in the risk of developing metabolic syndrome compared with women without PCOS, even after controlling for age and BMI, suggest-ing that PCOS alone is an independent risk factor for metabolic syndrome.33 Chen et al reported that the free androgen index, total testosterone and sex hormone-binding globulin levels are significantly correlated with

both systolic blood pressure and diastolic blood pres-sure in Taiwanese women with PCOS.34

6. Obesity and PCOS in Taiwanese Women

Obesity is a prominent feature of PCOS, occurring in 40–50% of those patients.8,35 Obesity appears to exert an additive, synergistic impact on the manifestations of PCOS, independently and negatively affecting in-sulin sensitivity, risk of diabetes and cardiovascular profile.36,37 The prevalence of obesity in PCOS patients is greater than that of the general female population. Conversely, the prevalence of PCOS is greater in over-weight and obese women than in lean women.38 Obes-ity worsens both biochemical hyperandrogenemia and chronic anovulation, which are the two most impor-tant diagnostic criteria of PCOS.38

In a study of women with PCOS, BMI had a signifi-cantly positive correlation with serum total testoster-one and a negative correlation with serum LH.35 This study also found that obese subjects with PCOS had a higher risk of developing oligomenorrhea [odds ratio (OR), 2.2; 95% confidence interval (CI), 1.3–3.7] and bio-chemical hyperandrogenemia (OR, 2.6; 95% CI, 1.6–4.2) than non-obese women with PCOS.35 Moreover, obese women with PCOS have significantly higher serum total testosterone levels, and more prolonged menstrual intervals than non-obese women with PCOS. Notably, obese women with PCOS present with less acne than non-obese subjects (OR, 0.5; 95% CI, 0.3–0.9).38 We re-cently studied 273 women in four phenotypes of PCOS and found that the insulin sensitivity index and the percentage of insulin resistance were not significantly different among discrete phenotypes of PCOS groups and normal controls. However, obesity (OR, 14.0; 95% CI, 7.5–26.5) results in a higher risk for developing insu-lin resistance than hyperandrogenemia (OR, 2.1; 95% CI, 1.3–3.6), oligomenorrhea (OR, 1.8; 95% CI, 1.0–3.3), and PCOM (OR, 1.4; 95% CI, 0.8–2.7).39 Compared with hyperandrogenemia, chronic anovulation, and PCOM, obesity is the most important risk factor in determining insulin resistance in women with PCOS. However, the average BMI is significantly lower in Taiwanese PCOS women than in Western women, which might partially explain the difference in clinical and biochemical pres-entations in women between East Asia and Western countries.8,17,39,40

7. Summary

The following points are summarized from this review. (1) PCOM is the most frequently used criterion in PCOS diagnosis. PCOS without androgen excess may be a mild phenotype of PCOS. (2) East Asian women with PCOS have a smaller mean ovarian volume and fewer mean

follicle numbers than Western women. (3) Hirsutism has a lower prevalence in Taiwanese women with PCOS than in Western women. (4) The LH to FSH ratio is a valuable diagnostic tool for evaluating Taiwanese women with PCOS, especially in the diagnosis of oligomenorrhea or anovulation. (5) Obese subjects with PCOS have a higher risk of developing oligomenorrhea, amenorrhea, bio-chemical HA, insulin resistance, and lower LH to FSH ratios than non-obese women with PCOS. (6) Taiwanese women with PCOS have a lower BMI and lower preva-lence of IGT than Western women with PCOS.

Acknowledgments

The authors would like to thank John Wheatley for his editorial assistance. This work was supported by a National Science Council grant (NSC 98-2629-B-038-001-MY3) from the Taiwan government, and a grant from the Wan-Fang Hospital at Taipei Medical University (grant 98TMU-WFH-05-2).

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