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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0628
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 8 4650-4658
Copyright © 2005 by The Endocrine Society

Health Care-Related Economic Burden of the Polycystic Ovary Syndrome during the Reproductive Life Span

Ricardo Azziz, Catherine Marin, Lalima Hoq, Enkhe Badamgarav and Paul Song

Department of Obstetrics and Gynecology (R.A., C.M.), Cedars-Sinai Medical Center, Los Angeles, California 90048; Departments of Obstetrics and Gynecology (R.A., C.M.) and Medicine (R.A.), The David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California 90095; and Cerner Health Insights (L.H., E.B., P.S.), Beverly Hills, California 90212

Address all correspondence and requests for reprints to: Ricardo Azziz, M.D., M.P.H., M.B.A., Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, 8635 West Third Street, Suite 160 W, Los Angeles, California 90048. E-mail: azzizr{at}cshs.org.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Context: The polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women today, affecting approximately 6.6% of unselected reproductive-aged women (~4 million women in the United States) (1990 National Institutes of Health criteria), and potentially represents a significant financial burden to our health care.

Objective: The objective of the study was to define, using current definitions and prevalence or incidence data, the minimal economic burden that PCOS in reproductive-aged women represents for the United States.

Design: The study design was a literature review.

Setting: The study was conducted at a tertiary care center.

Patients or Other Participants: There were no patients or other participants.

Intervention(s): We performed a systematic review of the published medical literature to identify studies evaluating epidemiology of reproductive-age PCOS and its clinical consequences and costs. We tied general societal cost data for the different health consequences to reproductive-age PCOS costs, using prevalence data.

Main Outcome Measure(s): The main measure in the study was total health care-related economic costs.

Results: We estimated the mean annual cost of the initial evaluation to be $93 million (2.1% of total costs), that of hormonally treating menstrual dysfunction/abnormal uterine bleeding to be $1.35 billion (31.0% of total), that of providing infertility care to be $533 million (12.2% of total), that of PCOS-associated diabetes to be $1.77 billion (40.5% of total), and that of treating hirsutism to be $622 million (14.2% of total).

Conclusions: The total cost of evaluating and providing care to reproductive-aged PCOS women in the United States is $4.36 billion. Because the cost of the diagnostic evaluation accounted for a relatively minor part of the total costs (approximately 2%), more widespread and liberal screening for the disorder appears be a cost-effective strategy, leading to earlier diagnosis and intervention and possibly the amelioration and prevention of serious sequelae.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE POLYCYSTIC OVARY syndrome (PCOS) was first described in the United States by Stein and Leventhal in 1935 (1) and since has been recognized as one of the most common endocrine disorders of women (2) and the most frequent cause of oligoovulatory infertility (3). PCOS is a heterogeneous disorder, whose principal features include androgen excess and ovulatory dysfunction. For the most part, PCOS appears to be inherited as a complex genetic trait (4).

Approximately 50–70% of patients with PCOS have detectable insulin resistance and hyperinsulinemia (5). In these patients hyperinsulinism stimulates androgen production by the ovaries (6) and suppression of SHBG (7, 8, 9). The metabolic associations of PCOS result in an increased risk for type 2 diabetes mellitus (DM) (5), dyslipidemia, hypertension, and cerebrovascular disease (10) and possibly cardiovascular morbidity (11). In addition, these metabolic abnormalities may result in an increased risk of obstetrical complications, including gestational DM (GDM), pregnancy-induced hypertension, and preeclampsia (12).

PCOS affects approximately one in 15 unselected women in the United States (2) and elsewhere (13, 14, 15), suggesting that there are approximately 105 million affected women aged 15–49 yr worldwide (16). Because of its high prevalence and association with ovulatory and menstrual abnormalities, infertility, hirsutism, and metabolic complications, this disorder potentially represents a significant financial burden to our health care. The objective of the present study was to define, using current definitions and prevalence or incidence data, the minimal economic burden that PCOS represents for the United States during the reproductive years. We first established the prevalence of the disorder among women of reproductive age in the United States; then assessed the prevalence of various morbidities associated with the disorder [menstrual dysfunction and abnormal uterine bleeding (AUB), endometrial abnormalities, infertility, type 2 DM, and hirsutism]; and finally calculated the economic impact of treating each of these morbidities, including the costs of the initial diagnostic evaluation, to arrive at an aggregate economic burden figure. Because the prevalence and morbidity of PCOS has been characterized mainly during the reproductive years, we will limit our analysis to determining the economic burden of the disorder during this part of the life span.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Definition of PCOS

The definition of PCOS most commonly used today arose from the proceedings of an expert conference sponsored by the National Institutes of Health (NIH) in April 1990, which concluded that PCOS was defined by (in order of importance): 1) hyperandrogenism and/or hyperandrogenemia, 2) ovulatory dysfunction, and 3) exclusion of related disorders such as hyperprolactinemia, thyroid disorders, and congenital adrenal hyperplasia (17). This definition is consistent with the proceedings of a more recent conference on the subject cosponsored by the European Society for Human Reproduction and Embryology and the American Society for Reproductive Medicine in May 2003 in Rotterdam, The Netherlands. For the purpose of this economic evaluation, we will primarily use the NIH 1990 diagnostic criteria, although we recognize that this may underestimate the true prevalence of the disorder.

Method of literature search and selection

We performed a systematic review of the published medical literature to identify studies evaluating PCOS and its clinical consequences, querying MEDLINE databases for English-language articles published between the years 1965 and 2004. Polycystic ovary syndrome, hypertension, diabetes, infertility, and gestational diabetes were used as medical subject headings, among other terms (Table 1Go). We also performed a hand search of bibliographies from relevant articles and reviews, and we solicited other references and opinions from experts in the field. We limited our search to human and English-language studies. We used general societal cost data for the different health consequences, tying them to PCOS costs using prevalence data found in our literature search. We limited our cost calculations to women through the reproductive life span.


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  		TABLE 1. PCOS literature search strategy

 
Explicit inclusion and exclusion criteria were developed for titles, abstracts, and articles. Two reviewers trained in health services research and the principles of critical appraisal independently reviewed random samples (10%) of the identified titles, abstracts, and full-text articles. Interrater agreement was assessed using the kappa statistic. A kappa of more than 0.7 was established as the threshold required for references to be divided between the two reviewers at each step in the review process. Disagreements between reviewers were resolved by consensus.

Articles were excluded at the title stage if they involved case reports, editorials, letters, or meeting abstracts. Full-text selected articles were reviewed and rejected if the studies did not report any of the outcomes of interest.

Estimating attributable costs

Drug costs. Drug costs were estimated from information in the 2005 Redbook (18).

Physician and procedure fees. Physician and procedure fees were estimated using the 2004 Centers for Medicare and Medicaid Services (CMS) physician fee schedules (19).

Laboratory fees. Laboratory fees were estimated from the CMS clinical laboratory fee schedules (20).

Adjusting for inflation. We adjusted for inflation using the consumer price index specific for medical services (21).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Prevalence of PCOS in reproductive-aged women

The prevalence of PCOS has been determined in various populations primarily of white or Caucasian race and, in one study, of African-American origin. In the United States, we initially reported that among 277 women seeking a preemployment physical in a university in the Southeast who were approximately evenly divided between whites and blacks, 4.0% had PCOS (22). In a subsequent, more detailed, study of 400 unselected consecutive women aged 18–45 yr in the same setting (223 black, 166 white, and 11 of other races) the overall prevalence of PCOS was observed to be 6.6%, and those for blacks and whites (8.0 and 4.8%, respectively) were not significantly different from the overall prevalence (2).

Using the 1990 NIH criteria, a study of 192 Greek women on the island of Lesbos and a study of 154 Caucasian female blood donors in Madrid found similar prevalences (6.8 and 6.5%, respectively) (14, 15). Likewise, among 230 volunteers (97% white) recruited from two Oxford universities and two general practice surgeries who agreed to participate in a study of women’s health issues, the prevalence of PCOS using the NIH 1990 criteria was reported to be 8% (13). The prevalence of clinically evident PCOS in unselected women of reproductive age ranged from 6.5 to 8.0% overall.

For the purposes of estimating the economic burden of the disorder in the United States, we will use a prevalence of PCOS of 6.6% in reproductive-aged women, using the 1990 NIH criteria. Considering that there are approximately 61,576,997 women aged 15–44 yr in the United States (23), we can then estimate that there are at least 4 million affected reproductive-aged women in the United States today.

Prevalence of principal morbidities associated with PCOS during the reproductive age

A number of reproductive, metabolic, and dermatologic morbidities have been associated with PCOS. In the following sections we establish the prevalence of the principal morbidities, including menstrual dysfunction/AUB, infertility, type 2 DM, and hirsutism.

Menstrual dysfunction and AUB. Per the NIH 1990 criteria (17), 100% of patients with PCOS are considered to be oligo/anovulatory, although not all patients demonstrate an overt abnormality in their cyclic vaginal bleeding pattern, the so-called periods. We should note that, whereas many patients and some practitioners refer to these bleeding episodes as menses, the strict definition of menstruation and menstrual cycles actually refers to the cyclic vaginal bleeding that results from the decline (withdrawal) in circulating estrogen and progestogen occurring at the end of the luteal phase of an ovulatory cycle in females who are not pregnant.

In a study of 132 consecutive women with hirsutism only, 73% of 93 oligoovulatory patients had menstrual dysfunction that they recognized (24), in agreement with other studies of hirsute women (25). Consistent with these data, in a larger series of patients diagnosed with PCOS by different methods, approximately 75–85% of PCOS women had clinically evident menstrual dysfunction (26, 27, 28). In a prospective study of PCOS patients diagnosed among 400 unselected women of the general population, approximately 60% of the patients had clinically evident menstrual dysfunction (2).

Overall between 60 and 85% of patients with PCOS exhibit overt menstrual dysfunction; therefore, we will use an average prevalence of 75% for calculating economic burden in the United States (see below).

Endometrial hyperplasia and carcinoma. In addition to menstrual dysfunction and infertility, women with PCOS may be at increased risk for endometrial hyperplasia (29, 30) and carcinoma (31, 32, 33). However, the prevalence of these endometrial abnormalities in PCOS is still unclear due to the paucity of large-scale screening studies and the small number of patients actually identified with carcinoma (32).

Current diagnostic standards suggest that an endometrial biopsy, particularly if the endometrial thickness on sonography is above 4–8 mm in thickness, should be an integral part of the evaluation of women at moderate risk for endometrial cancer. This includes women who are younger than age 40 yr with additional risk factors such as PCOS (34). In a small study, Cheung (29) evaluated 36 patients with PCOS by endometrial biopsy and observed that 35.7% had endometrial hyperplasia and 25% of these had cytological atypia.

Consequently, whereas we will not consider the prevalence or cost of treating endometrial abnormalities in PCOS in our calculation of economic burden, we will consider the costs of a screening transvaginal ultrasound and possibly an endometrial biopsy in calculating the costs of the initial evaluation of these patients (see below).

Infertility. As noted above, per the NIH 1990 criteria (17), 100% of patients with PCOS are considered to suffer from ovulatory dysfunction, which reduces their overall fecundability. However, we should note that not all patients with PCOS are absolutely infertile, and many women with PCOS patients will ovulate intermittently. In a study of more than 300 PCOS women included in a prospective trial designed to study the effectiveness of troglitazone for the treatment of ovulatory dysfunction, among patients treated with a placebo, 32% ovulated over the 6 months of the study (35). Whether patients with PCOS will suffer from infertility will depend on ovulatory rate, coital frequency, presence of concomitant infertility factors, overall expectations for fecundability and family size, and ultimately the desire for children. Overall, between 33 and 75% of PCOS patients report having infertility (2, 36, 37), a variation largely explained by clinic referral or ascertainment bias.

Overall we can estimate that 50% of PCOS patients will actively seek infertility services at some point in their lifetime, a figure we will use for our calculations of economic burden of PCOS (see below).

Type 2 DM. In three studies of large populations of consecutive women with PCOS in the United States with average ages ranging from 28 to 30 yr, the prevalence of type 2 DM ranged from 4 to 10%, respectively (38, 39, 40). These data agree with those of an analysis of data from the Nurses’ Health Study II, a prospective observational cohort study, including a total of 101,073 women who had no prior history of DM and who reported their usual menstrual cycle pattern at age 18–22 yr on the baseline (1989) questionnaire (41). This study demonstrated that women with long or highly irregular menstrual cycles, and many presumably with PCOS, had an approximately 2-fold increased risk for developing type 2 DM not completely explained by obesity. Overall these data indicate that women with PCOS are at a 2- to 6-fold higher risk of developing type 2 DM, compared with age-matched average women, whose prevalence of type 2 DM is 1.6–2.0% (42, 43). For our calculations of economic burden, we will consider PCOS patients as having a 4-fold greater risk of type 2 DM than comparably aged women.

Considering that comparably aged women of the general population have a prevalence of 1.8%, the overall prevalence of type 2 DM in PCOS can be estimated to be 7.2% during the reproductive years, a figure we will use in calculating economic burden (see below).

Hirsutism. Hirsutism is the growth of excess terminal hair on the face or body in a male-like pattern in women. Between 50 and 75% of black or white PCOS women in the United States demonstrate hirsutism (17). Likewise, our report of PCOS subjects diagnosed prospectively among 400 unselected women of the general population indicated that 76% were hirsute (2). We should note that the prevalence and degree of hirsutism is dependent on the ethnicity of the patients, being less prevalent in PCOS women of East Asian extraction or Pacific Islanders (44, 45) but more prevalent in women of Asian Indian origin (e.g. Bengali, Gujarati, or Dravidian Indian) (46).

Because only 3.6% of the U.S. population is Asian (23), we will use the hirsutism prevalence observed in white and black women, approximately 70%, for our calculations.

Estimating the economic burden of PCOS during the reproductive years

To calculate the current minimal lifetime economic burden of PCOS, we will first consider that at least 4 million women are affected with this disorder in the United States today. We will then consider the costs of the initial diagnostic evaluation of these patients and the prevalences and costs of treating their infertility, menstrual dysfunction, type 2 DM, and hirsutism (Table 2Go).


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  		TABLE 2. Estimates of the prevalence of morbidities1 associated with PCOS in the United States used for calculation of economic burden

 
Cost of the initial diagnosis and evaluation. The initial evaluation of a patient suspected of PCOS may include, at a minimum (47, 48): a testosterone panel (total and free or bioactive testosterone) and dehydroepiandrosterone sulfate, at least in the 25% of PCOS women who are not overly hirsute and TSH, prolactin, and 17-hydroxyprogesterone (17-HP) in all patients suspected of having PCOS to screen for thyroid disorders, hyperprolactinemia, and 21-hydroxylase-deficient nonclassic adrenal hyperplasia, respectively (Table 3Go). Approximately 6% of PCOS patients will have an elevated screening 17-HP level (i.e. > 2 ng/ml) and will require an acute ACTH stimulation test to exclude nonclassic adrenal hyperplasia (49). A transvaginal sonogram should also be performed in all patients, both to assess for the presence of polycystic ovaries (48) and evaluate the endometrial thickness as a screen for excessive endometrial thickening, determining the need for an endometrial biopsy (29).


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  		TABLE 3. Cost of the initial evaluation of patients with PCOS in 2004 dollars

 
We also include the cost of performing the endometrial biopsy in selected PCOS patients. Overall, we estimate that approximately 30% of PCOS patients will merit an endometrial biopsy, either because they demonstrate amenorrhea or have an endometrial thickness of greater than 7 mm on ultrasonography (29). Metabolic evaluation, including basal and 2-h glucose and insulin levels after the oral administration of 75 g glucose, and a lipid profile should also be performed in all patients with PCOS, considering the high prevalence of glucose intolerance, hyperinsulinemia, and metabolic syndrome among these women (5).

Overall, the average cost of the initial evaluation of patients with PCOS is $740 (Table 3Go). Assuming that all PCOS patients are evaluated at least once in their lifetime and that the demand for a diagnostic evaluation is uniformly distributed over the reproductive life span (i.e. 30 yr), we can estimate that the average annual cost of the initial evaluation of PCOS patients is approximately $99 million [i.e. (4 million patients x $740/patient)/30 yr] (Table 4Go).


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  		TABLE 4. The overall health care-related economic burden of PCOS patients during their reproductive years in 2004

 
Cost of treating menstrual dysfunction or AUB. For this estimation we will assume that all PCOS patients who suffer AUB and do not desire pregnancy will be treated hormonally with an oral contraceptive (OC) and that treatment with an OC will require one additional physician office visit per year (50). Assuming an average cost of $30 per 28-d OC pack, (18) with one additional physician visit annually for menstrual-related concerns averaging $60.00/visit (based on a 99212 current procedural terminology code denoting an established outpatient visit for a self-limited or minor condition) (19), we can estimate that the annual cost of treating menstrual dysfunction/AUB is $450.00 (note that 13 28-d OC packs are used yearly), a cost similar to that reported by others for the treatment of other menstrual disorders (50).

Consequently, assuming that 75% of PCOS patients at any one time will require hormonal treatment for menstrual dysfunction/AUB (with the remainder either seeking fertility or not having symptoms sufficient to incite treatment), we can estimate that the annual cost of hormonally treating menstrual dysfunction/AUB in PCOS patients is approximately $1.4 billion (i.e. 4 million patients x 75% x $450/yr) (Table 4Go).

Cost of evaluating and treating infertility. Infertility treatment can be as simple as a course of ovulation induction with clomiphene citrate (50 mg/d x 5 d/month) or metformin (2000 mg/d continuously) at a cost of $50 per treatment cycle up to an average cost of $9226 per cycle of in vitro fertilization (51). For patients treated using a standard infertility treatment algorithm, the cost per live pregnancy was variously reported as $9557 in Chicago, Illinois (52) and $5648 in Birmingham, Alabama (53), both estimates obtained in 1997. From these studies we can estimate that the average cost per pregnancy using a standard infertility treatment algorithm, adjusted for inflation, can be projected to be approximately $8000.

We have estimated that approximately 50% of patients with PCOS will seek infertility care at some point in their lives. Assuming that demand for infertility evaluation and treatment is uniformly distributed over the reproductive lifespan (i.e. 30 yr), we can estimate the average annual cost of infertility care for PCOS patients as $533 million [i.e. (4 million patients x 50% seeking infertility during their lifetime x $8000/patient)/30 yr] (Table 4Go).

Cost of treating type 2 DM. Direct medical expenditures attributable to diabetes totaled $132 billion in 2002, assuming a total of 12.1 million affected patients (54). Costs for individuals younger than 45 yr of age, numbering 2.1 million, were estimated to be a total of $12.6 billion. Because 52% of all affected patients were women, we can estimate that a total of $6.5 billion was spent in 2002 for the care of diabetic women under the age of 45 yr, or $5995 per affected patient ($6133 per patient in 2003 figures).

We have estimated that the prevalence of diabetes in reproductive-aged PCOS women is 7.2%; consequently, the economic burden of PCOS-associated diabetes during the reproductive years can be estimated as $1.77 billion annually (i.e. 4 million patients x 7.2% x $6133/yr) (Table 4Go).

Cost of treating hirsutism. Treatment of hirsutism encompasses both cosmetic and hormonal therapies. We have reported that approximately 50% of hirsute PCOS women will have undergone electrology at some time in their lives, based on a study of 257 patients with androgen excess (2). We can conservatively estimate that the cost of electrology for the treatment of a moderately hirsute patient approximates $10,800 in current dollars (12 months of treatment, 300 min/month, $3/min; Kirby P, CPE, executive director, American Electrology Association, personal communication). Assuming that treatment is uniformly distributed over the reproductive span (i.e. 30 yr), we can estimate an average annual cost of electrology of $360 (i.e. $10,800/30) for patients ever having undergone electrology.

Concomitant hormonal blockade with an antiandrogen should be used in all women with hirsutism. Using 100 mg/d of the antiandrogen spironolactone as the measure, the cost of this regimen averages $164.25/yr (i.e. 365 tablets of 100 mg spironolactone at $0.45 each) (18). Whereas continued hormonal suppression may be required, it is also probable that the degree of hirsutism lessens over time because ovarian and adrenal androgen biosynthesis and circulating androgen levels decline with age (55, 56, 57). Furthermore, the need for antiandrogen therapy should diminish in those hirsute women who are also treated by electrology and possibly laser therapy. Consequently, our calculations will estimate that spironolactone is used only for an average of 5 yr during the reproductive stage of life.

Because we have estimated that 70% of PCOS patients in the United States are hirsute, that 50% will use electrology at some point in their lives, and that spironolactone will be used at a dose of 100 mg/d for an average of 5 yr, we can calculate the average annual cost of treating hirsutism in PCOS as being more than $600 million annually [i.e. 4 million patients x 75% x {[$164.25/yr x 5/30 yr] + [$360 x 50%]}] (Table 4Go).

Overall economic burden. The economic burden of PCOS among those aged 14–44 yr can conservatively be calculated to be approximately $4.37 billion annually (Table 4Go). Approximately 40% of the burden is due to the increased prevalence of diabetes associated with PCOS; 31% from the treatment of the associated menstrual dysfunction/AUB, 14% from the treatment of hirsutism, and 12% for the provision of infertility services. The costs of a single diagnostic evaluation for each patient accounted for a relatively small portion of the calculated health care-related economic burden, approximately 2%.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
PCOS affects 6–7% of unselected women of reproductive age and is associated with increased risks for infertility, menstrual dysfunction, type 2 DM, and hirsutism, among other problems. The costs of evaluating for PCOS and its associated morbidities, and treating the associated long-term morbidities, exceed $4 billion annually in 2004 dollars in the United States alone. This estimate should be considered to be relatively conservative because it takes into account only the costs of evaluating and caring for the patient during her reproductive years, although much of the associated morbidity (e.g. cardiovascular disease and type 2 DM) may present in the postreproductive years. Furthermore, we have included only those complications that are well established as being associated with the disorder, excluding other abnormalities (e.g. obstetrical complications, endometrial cancer, dyslipidemia, hypertension and other cardiovascular disease, and depression) for which data are strongly suggestive but not conclusive of a relationship. The annual burden of evaluating and treating PCOS patients in the United States during their reproductive years is approximately 3-fold that of hepatitis C ($1 billion in 1998) (58) and approximately one third that of morbid obesity ($11 billion in 2000) (59). It is also likely that this estimate will rise as the prevalences of postreproductive morbidities of PCOS are better established.

The cost of diagnosing and initially evaluating patients for PCOS represented only 2.1% of the total economic burden calculated. This estimate does not include the cost of repeat testing or office visits or the cost of screening those individuals who will eventually be found to be unaffected. Because the cost of the diagnostic evaluation for PCOS accounts for a relatively minor part of the total costs, these data would suggest that the formulation of more liberal patient screening programs is a cost-effective approach to reducing long-term morbidity by fostering the early identification of endometrial hyperplasia, excess terminal hair growth, glucose intolerance, obesity, and insulin resistance.

The economic burden of menstrual dysfunction or AUB in PCOS represented approximately one third of the overall costs estimated, which is not surprising because menstrual dysfunction is an almost universal feature and complaint of PCOS patients. We should note that this estimate does not factor in the cost of repeated diagnostic procedures (e.g. endometrial biopsy and sonography, which were included only as one-time procedures in the estimated costs of the initial evaluation of the PCOS patient) or surgical procedures needed for diagnosis and treatment (e.g. hysteroscopy, dilatation and curettage, or hysterectomy). It also does not include the cost of: 1) any treatments occurring before the diagnosis of PCOS is established; 2) hygienic products (e.g. sanitary pads and tampons); 3) other medications possibly used, such as insulin sensitizers; 4) home pregnancy tests; 5) medications for pain relief and iron replacement therapy (for treating menstrual pains and anemia, respectively); and 6) indirect expenditures, such as daily wage losses from women staying home from work to manage uterine bleeding-associated symptoms and the opportunity costs of physician visits. For example, heavy menstrual bleeding alone was estimated to contribute an estimated $1692 in expected lost wages per affected woman and a 6.9% reduction in total employment per year (60).

The cost of infertility care represented approximately 12% of total expenditures. This estimate did not consider whether PCOS patients would have a more or less difficult (i.e. more or less expensive) course of treatment than the average infertile patient. This estimate also does not take into account the greater frequency of complications often observed in PCOS, including an increased risk for developing GDM (12, 61, 62, 63), preeclampsia, and pregnancy-induced hypertension (12, 62, 64, 65, 66, 67, 68, 69), and possibly miscarriage (70, 71, 72, 73, 74, 75).

Not surprisingly, the costs of type 2 DM represent approximately 40% of the entire economic burden attributable to PCOS, although we did not include those costs related to an increased incidence of GDM. We should note that the risks of impaired glucose tolerance and type 2 DM in PCOS increase with age (76), degree of obesity (10, 39, 76), and family history for diabetes (39, 40). The increased risk for type 2 DM observed in PCOS women reflects, to a significant degree, the high prevalence of obesity observed in these patients (10, 76). For example, 90% of diabetic PCOS patients diagnosed in the study by Legro et al. (76), who assessed 254 patients diagnosed either at the Pennsylvania State University College of Medicine or Mount Sinai School of Medicine, had a body mass index (BMI) of 30 kg/m2 or greater. When the risk of type 2 DM in PCOS was adjusted for BMI, the increased prevalence of diabetes was no longer significantly different from controls, at least in one study assessing 319 women with PCOS and 1060 controls (10).

We have not included the costs of lifestyle intervention for the prevention of diabetes in this study because this is an analysis of the economic burden of the disease itself, not interventions designed to potentially ameliorate its morbidity, other than the initial diagnostic maneuvers. However, we note that a study by the Diabetes Prevention Program reported that the direct medical cost of intensive lifestyle intervention for the prevention of diabetic complications in at-risk individuals was $1399, $679, and $702 per subject in yr 1–3, respectively (77). We can then estimate that if the average cost of intensive lifestyle modification is approximately $800/yr per subject, an additional $3.2 billion in expenses may be incurred, although these costs should be offset by whatever net savings may arise from the implementation of these maneuvers, a figure we currently do not have.

Cardiovascular disease (CVD), including coronary heart disease (CHD), stroke, and peripheral artery disease, is the leading cause of death in the United States, affecting 6% of the overall population (78). Risk factors for CVD include hyperlipidemia, hypertension, diabetes, and obesity, all of which are present in PCOS; and several studies have found higher rates of CVD risk factors in women with PCOS when compared with a control group (10, 79, 80, 81). These data also agree with those of an analysis of the Nurses’ Health Study population, which included 82,439 women who provided information in 1982 on prior menstrual regularity (at ages 20–35 yr) and were followed up through 1996 for cardiovascular events (82). This study demonstrated that women with long or highly irregular menstrual cycles and many presumably with PCOS had a 25–67% increased age-adjusted risk for nonfatal or fatal CHD, compared with women reporting a history of very regular menstrual cycles; this difference remained significant after adjustment for BMI and several potential confounders.

However, we should note that the evidence suggesting that the incidence of premature CHD is higher in the PCOS population is conflicting. A higher prevalence of coronary artery and aortic calcification (83), an increase in left ventricular mass index (84), a decrease in diastolic filling (84), a significantly lower flow-mediated dilation (85), and a higher intima-media thickness (85) have been observed in PCOS. However, Legro (11) reviewed the current available evidence for an association between PCOS and CVD and noted that, whereas existing data suggested that PCOS may adversely affect or accelerate the development of an adverse cardiovascular risk profile and even of subclinical signs of atherosclerosis, it did not appear to lower the age of clinical presentation to a premenopausal age group.

Supporting the apparently modest role of PCOS in premature CHD, a study of 346 PCOS Dutch subjects did not reveal a significantly higher prevalence of cardiac complaints (serious heart disease or cardiac arrest) when compared with the general Dutch population (86). Likewise, Pierpoint et al. (87) did not observe a significantly higher prevalence of CHD-related mortality among 786 PCOS women evaluated an average of 30 yr after diagnosis, compared with national rates. These findings were in agreement with another study in the same population, which indicated that the prevalence of CHD among 319 PCOS women surveyed a mean of 31 yr after diagnosis was not significantly greater than that of 1060 age-matched controls (4.7 vs. 4.0%, respectively) (10). This latter study, however, did demonstrate a significant increase in the incidence of cerebrovascular disease in PCOS, compared with controls (3.1 vs. 1.2%, respectively) (10), although this association remains to be confirmed by other investigators. It is possible that the lack of a significant association of PCOS with CVD- or CHD-related events or mortality in these studies may be due to the short length of follow-up of the studies or the relatively young age of the PCOS patients at the time of follow-up. Overall, there are currently limited data to suggest that the incidence of CVD-associated events or mortality is actually higher in reproductive-aged PCOS patients, compared with age-matched controls. Consequently, the present analysis did not include these morbidities in our calculations of economic burden.

Patients with PCOS frequently develop androgen-related dermatologic complaints, including hirsutism, acne, and androgenic alopecia, which have significant psychosocial and quality-of-life implications (88, 89) and economic impact. In calculating the economic burden of hirsutism, which accounted for approximately 14% of all costs, we did not include the costs of concomitant ovarian suppression, such as OC pills, because we are assuming that most PCOS patients not seeking fertility will be treated with an OC pill for the control of menstrual dysfunction. Whereas we estimated the costs of electrology, we did not include laser hair removal because it is not yet clear that the latter technique provides permanent hair destruction (90). In addition, this estimate did not consider the cost of electrology beyond the first year of treatment or the cost of other dermatologic treatments, including depilation, bleaching, shaving, cosmetics (i.e. makeup), or the 13.9% eflornithine hydrochloride cream (Vaniqa, SkinMedica, Inc., Carlsbad, CA).

Acne affects approximately 12–14% of white PCOS patients (2, 46), although the prevalence of this dermatologic abnormality varies with ethnicity: it is reportedly higher in Asian Indians (46) and lower in Pacific Islanders (44). Androgenic alopecia is also a recognized sign of PCOS (26, 28, 91, 92, 93), although the prevalence of this abnormality in the disorder is unclear. In a study of 257 patients who were compliant with treatment and follow-up, only 12 (4.7%) complained of hair loss (26). Due to the apparent relatively low prevalence of acne and androgenic alopecia in PCOS, we did not include these abnormalities in our calculations of economic burden.

Overall, the present analysis has a number of strengths: it uses clearly established prevalences and costs to arrive at the economic burden calculated. Nonetheless, we must recognize potential limitations, including the fact that it was difficult to estimate the total lifetime cost of PCOS due to the paucity of follow-up data in large populations of PCOS women. Our study design was also limited by the need to extrapolate cost estimates from those of the general population because there were limited data on the costs of providing services to PCOS patients. In addition, we relied on the best estimates of point prevalences of the clinical consequences to give us a broad economic picture. This method of cost extrapolation has been used previously in the literature in which prevalence or incidence data are combined with general population cost data to estimate the economic burden of illness of diseases or conditions (94, 95). The indirect costs due to lost productivity and diminished quality of life were also very hard to tie in to the overall cost estimates, which often led to underestimation of the true cost of the disease.

It is likely that the present analysis underestimates the true health care-related economic burden of PCOS. We have already indicated that we were not able to calculate the lifelong impact of the disorder or the costs of a number of morbidities or potential expenses, including the more recent use of insulin sensitizers. However, underestimation may also stem from how the overall prevalence of the disorder was defined. We used prevalence figures derived using a relatively narrow definition of PCOS, which was advocated by an expert conference sponsored by the NIH in 1990 (17). New criteria proposed by an expert conference held in Rotterdam in 2003 expanded the definition of PCOS (48). Finally, our calculations are based on disease prevalence data determined primarily in white or black subjects (2, 13, 14, 15), although the prevalence may be higher in other ethnic groups (96).

Alternatively, a few factors in our analysis may have led to overestimation of the economic burden. Most importantly, our calculations assumed that all PCOS patients would seek and be willing to undergo the required evaluations and treatments. Unfortunately, current data suggest that only approximately 30% of all patients with the disorder will seek care (97, 98). Considering the relatively low cost of the evaluation, compared with the cost of treating the associated morbidities, this would appear to represent an excellent opportunity for improvement.

In conclusion, the costs of evaluating and caring for PCOS patients during their reproductive years can be conservatively estimated to exceed $4 billion, although this estimate would be significantly higher if the costs of caring for morbidities emerging in the postreproductive years were considered. The cost of the diagnostic evaluation accounts for a relatively minor part of the costs, slightly more than 2%. This suggests that more widespread screening for the disorder is potentially a cost-effective strategy, leading to earlier diagnosis and intervention and possibly the amelioration and prevention of serious sequelae. Patients with PCOS have a 4-fold increased risk of developing type 2 DM, and approximately 40% of the economic burden is due to the development of this morbidity in these patients during their reproductive years. We can estimate that 12.8% of the $12.6 billion associated with the management of diabetes of patients younger than 45 yr old is attributed to women with PCOS (54). The conservative management of menstrual dysfunction or AUB accounts for approximately one third of all costs, which is not surprising because a majority of patients with PCOS demonstrate this abnormality. Considering the low cost of diagnosis and the high cost of the associated morbidities, aggressive identification of PCOS and prompt and early management of the associated clinical consequences represent a cost-effective strategy to reduce the considerable economic burden of this disorder.


   Footnotes
 
This work was supported in part by a grant from the Cedars-Sinai Health System and Grants RO1-HD29364 and K24-D01346 from the National Institutes of Health (to R.A.).

First Published Online June 8, 2005

Abbreviations: AUB, Abnormal uterine bleeding; BMI, body mass index; CHD, coronary heart disease; CVD, cardiovascular disease; DM, diabetes mellitus; GDM, gestational DM; 17-HP, 17-hydroxyprogesterone; OC, oral contraceptive; PCOS, polycystic ovary syndrome.

Received March 22, 2005.

Accepted May 26, 2005.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Stein IF, Leventhal NL 1935 Amenorrhea associated with bilateral polycystic ovaries. Am J Obstet Gynecol 29:181–191
  2. Azziz R, Woods KS, Reyna R, Key TJ, Knochenhauer ES, Yildiz BO 2004 The prevalence and features of the polycystic ovary syndrome in an unselected population. J Clin Endocrinol Metab 89:2745–2749[Abstract/Free Full Text]
  3. Hull MG 1981 Ovulation failure and induction. Clin Obstet Gynaecol 8:753–785[Medline]
  4. Legro RS 2000 The genetics of obesity. Lessons for polycystic ovary syndrome. Ann NY Acad Sci 900:193–202[Abstract/Free Full Text]
  5. Ovalle F, Azziz R 2002 Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus. Fertil Steril 77:1095–1105[CrossRef][Medline]
  6. Nestler JE 1997 Role of hyperinsulinemia in the pathogenesis of the polycystic ovary syndrome, and its clinical implications. Semin Reprod Endocrinol 15:111–122[Medline]
  7. Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, Clore JN, Blackard WG 1991 A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab 72:83–89[Abstract]
  8. Plymate SR, Jones RE, Matej LA, Friedl KE 1988 Regulation of sex hormone binding globulin (SHBG) production in Hep G2 cells by insulin. Steroids 52:339–340[CrossRef][Medline]
  9. Plymate SR, Matej LA, Jones RE, Friedl KE 1988 Inhibition of sex hormone-binding globulin production in the human hepatoma (Hep G2) cell line by insulin and prolactin. J Clin Endocrinol Metab 67:460–464[Abstract]
  10. Wild S, Pierpoint T, McKeigue P, Jacobs H 2000 Cardiovascular disease in women with polycystic ovary syndrome at long-term follow-up: a retrospective cohort study. Clin Endocrinol (Oxf) 52:595–600[CrossRef][Medline]
  11. Legro RS 2003 Polycystic ovary syndrome and cardiovascular disease: a premature association? Endocr Rev 24:302–312[Abstract/Free Full Text]
  12. Bjercke S, Dale PO, Tanbo T, Storeng R, Ertzeid G, Abyholm T 2002 Impact of insulin resistance on pregnancy complications and outcome in women with polycystic ovary syndrome. Gynecol Obstet Invest 54:94–98[CrossRef][Medline]
  13. Michelmore KF, Balen AH, Dunger DB, Vessey MP 1999 Polycystic ovaries and associated clinical and biochemical features in young women. Clin Endocrinol (Oxf) 51:779–786[CrossRef][Medline]
  14. Diamanti-Kandarakis E, Kouli CR, Bergiele AT, Filandra FA, Tsianateli TC, Spina GG, Zapanti ED, Bartzis MI 1999 A survey of the polycystic ovary syndrome in the Greek island of Lesbos: hormonal and metabolic profile. J Clin Endocrinol Metab 84:4006–4011[Abstract/Free Full Text]
  15. Asuncion M, Calvo RM, San Millan JL, Sancho J, Avila S, Escobar-Morreale HF 2000 A prospective study of the prevalence of the polycystic ovary syndrome in unselected Caucasian women from Spain. J Clin Endocrinol Metab 85:2434–2438[Abstract/Free Full Text]
  16. Population Reference Bureau 2002 World population data sheet of the population reference bureau: demographic data and estimates for the countries and regions of the world. Washington, DC: Population Reference Bureau
  17. 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 Publications; 377–384
  18. 2004 Drug topics red book. 108th ed. Stamford, CT: Thomson Healthcare
  19. Centers for Medicare and Medicaid Services 2004 Centers for Medicare and Medicaid Services (CMS) physician fee schedules. Available at: http://www.cms.hhs.gov/physicians/mpfsapp/display.asp
  20. Centers for Medicare and Medicaid Services 2005 Clinical laboratory fee schedules. Baltimore, MD: Centers for Medicare and Medicaid Services
  21. U.S. Department of Labor 2005 Consumer price index: all urban consumers (Medical Care Services). Washington DC: Bureau of Labor Statistics, Division of Consumer Prices and Price Indexes
  22. Knochenhauer ES, Key TJ, Kahsar-Miller M, Waggoner W, Boots LR, Azziz R 1998 Prevalence of the polycystic ovary syndrome in unselected black and white women of the southeastern United States: a prospective study. J Clin Endocrinol Metab 83:3078–3082[Abstract/Free Full Text]
  23. U.S. Census Bureau Census 2000 Summary file 1, QT-P3. Washington DC: U.S. Census Bureau, Population Division
  24. Azziz R, Waggoner WT, Ochoa T, Knochenhauer ES, Boots LR 1998 Idiopathic hirsutism: an uncommon cause of hirsutism in Alabama. Fertil Steril 70:274–278[CrossRef][Medline]
  25. Carmina E 1998 Prevalence of idiopathic hirsutism. Eur J Endocrinol 139:421–423[Abstract]
  26. Azziz R, Sanchez LA, Knochenhauer ES, Moran C, Lazenby J, Stephens KC, Taylor K, Boots LR 2004 Androgen excess in women: experience with over 1000 consecutive patients. J Clin Endocrinol Metab 89:453–462[Abstract/Free Full Text]
  27. Goldzieher JW, Axelrod LR 1963 Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 14:631–653[Medline]
  28. Conway GS, Honour JW, Jacobs HS 1989 Heterogeneity of the polycystic ovary syndrome: clinical, endocrine and ultrasound features in 556 patients. Clin Endocrinol (Oxf) 30:459–470[Medline]
  29. Cheung AP 2001 Ultrasound and menstrual history in predicting endometrial hyperplasia in polycystic ovary syndrome. Obstet Gynecol 98:325–331[Abstract/Free Full Text]
  30. Chamlian DL, Taylor HB 1970 Endometrial hyperplasia in young women. Obstet Gynecol 36:659–666[Abstract/Free Full Text]
  31. Balen A 2001 Polycystic ovary syndrome and cancer. Hum Reprod Update 7:522–525[Abstract/Free Full Text]
  32. Hardiman P, Pillay OC, Atiomo W 2003 Polycystic ovary syndrome and endometrial carcinoma. Lancet 361:1810–1812[CrossRef][Medline]
  33. Dockerty MB, Jackson RL 1957 The Stein-Leventhal syndrome: analysis of 43 cases with special reference to association with endometrial carcinoma. Am J Obstet Gynecol 73:161–173[Medline]
  34. Critchley HO, Warner P, Lee AJ, Brechin S, Guise J, Graham B 2004 Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status. Health Technol Assess 8:iii-iv, 1–139
  35. Azziz R, Ehrmann D, Legro RS, Whitcomb RW, Hanley R, Fereshetian AG, O’Keefe M, Ghazzi MN 2001 Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial. J Clin Endocrinol Metab 86:1626–1632[Abstract/Free Full Text]
  36. Balen AH, Conway GS, Kaltsas G, Techatrasak K, Manning PJ, West C, Jacobs HS 1995 Polycystic ovary syndrome: the spectrum of the disorder in 1741 patients. Hum Reprod 10:2107–2111[Abstract/Free Full Text]
  37. Goldzieher JW 1981 Polycystic ovarian disease. Fertil Steril 35:371–394[Medline]
  38. Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrmann DA 2002 Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymorphism in the PPAR{gamma} gene. J Clin Endocrinol Metab 87:772–775[Abstract/Free Full Text]
  39. Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J 1999 Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care 22:141–146[Abstract/Free Full Text]
  40. Ehrmann DA, Kasza K, Azziz R, Legro RS, Ghazzi MN 2005 Effects of race and family history of type 2 diabetes on metabolic status of women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:66–71[Abstract/Free Full Text]
  41. Solomon CG, Hu FB, Dunaif A, Rich-Edwards J, Willett WC, Hunter DJ, Colditz GA, Speizer FE, Manson JE 2001 Long or highly irregular menstrual cycles as a marker for risk of type 2 diabetes mellitus. JAMA 286:2421–2426[Abstract/Free Full Text]
  42. Harris MI, Hadden WC, Knowler WC, Bennett PH 1987 Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in U.S. population aged 20–74 yr. Diabetes 36:523–534[Abstract]
  43. Schiller JS, Coriaty Nelson Z, Hao C, Barnes P 2004 Early release of selected estimates based on data from the January-March 2004 National Health Interview Survey. National Center for Health Statistics. March, 2005
  44. Williamson K, Gunn AJ, Johnson N, Milsom SR 2001 The impact of ethnicity on the presentation of polycystic ovarian syndrome. Aust N Z J Obstet Gynaecol 41:202–206[Medline]
  45. 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]
  46. Wijeyaratne CN, Balen AH, Barth JH, Belchetz PE 2002 Clinical manifestations and insulin resistance (IR) in polycystic ovary syndrome (PCOS) among South Asians and Caucasians: is there a difference? Clin Endocrinol (Oxf) 57:343–350[CrossRef][Medline]
  47. Azziz R 2000 The time has come to simplify the evaluation of the hirsute patient. Fertil Steril 74:870–872[CrossRef][Medline]
  48. Rotterdam ESHRE/ASRM-sponsored PCOS Consensus Workshop Group 2004 Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 81:19–25[Medline]
  49. Azziz R, Hincapie LA, Knochenhauer ES, Dewailly D, Fox L, Boots LR 1999 Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study. Fertil Steril 72:915–925[CrossRef][Medline]
  50. Braunstein JB, Hausfeld J, Hausfeld J, London A 2003 Economics of reducing menstruation with trimonthly cycle oral contraceptive therapy: comparison with standard-cycle regimens. Obstet Gynecol 102:699–708[Abstract/Free Full Text]
  51. Katz P, Nachtigall R, Showstack J 2002 The economic impact of the assisted reproductive technologies. Nat Med 8(Suppl):S29–S32
  52. Karande VC, Korn A, Morris R, Rao R, Balin M, Rinehart J, Dohn K, Gleicher N 1999 Prospective randomized trial comparing the outcome and cost of in vitro fertilization with that of a traditional treatment algorithm as first-line therapy for couples with infertility. Fertil Steril 71:468–475[CrossRef][Medline]
  53. Blackwell RE, Hammond KR, Steinkampf MP 2001 A one-year experience with a capitated health care plan for infertility. Fertil Steril 75:749–753[CrossRef][Medline]
  54. Hogan P, Dall T, Nikolov P 2003 Economic costs of diabetes in the U.S. in 2002. Diabetes Care 26:917–932[Abstract/Free Full Text]
  55. Moran C, Azziz R, Carmina E, Dewailly D, Fruzzetti F, Ibanez L, Knochenhauer ES, Marcondes JA, Mendonca BB, Pignatelli D, Pugeat M, Rohmer V, Speiser PW, Witchel SF 2000 21-Hydroxylase-deficient nonclassic adrenal hyperplasia is a progressive disorder: a multicenter study. Am J Obstet Gynecol 183:1468–1474[CrossRef][Medline]
  56. Winters SJ, Talbott E, Guzick DS, Zborowski J, McHugh KP 2000 Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome. Fertil Steril 73:724–729[CrossRef][Medline]
  57. Piltonen T, Koivunen R, Perheentupa A, Morin-Papunen L, Ruokonen A, Tapanainen JS 2004 Ovarian age-related responsiveness to human chorionic gonadotropin in women with polycystic ovary syndrome. J Clin Endocrinol Metab 89:3769–3775[Abstract/Free Full Text]
  58. Kim WR 2002 The burden of hepatitis C in the United States. Hepatology 36:S30–S34
  59. Arterburn DE, Maciejewski ML, Tsevat J 2005 Impact of morbid obesity on medical expenditures in adults. Int J Obes Relat Metab Disord 29:334–339[CrossRef][Medline]
  60. Cote I, Jacobs P, Cumming D 2002 Work loss associated with increased menstrual loss in the United States. Obstet Gynecol 100:683–687[Abstract/Free Full Text]
  61. Ciampelli M, Fulghesu AM, Lanzone A 1999 Comment on "Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome." J Clin Endocrinol Metab 84:2974–2975[Free Full Text]
  62. Mikola M, Hiilesmaa V, Halttunen M, Suhonen L, Tiitinen A 2001 Obstetric outcome in women with polycystic ovarian syndrome. Hum Reprod 16:226–229[Abstract/Free Full Text]
  63. Wortsman J, de Angeles S, Futterweit W, Singh KB, Kaufmann RC 1991 Gestational diabetes and neonatal macrosomia in the polycystic ovary syndrome. J Reprod Med 36:659–661[Medline]
  64. Radon PA, McMahon MJ, Meyer WR 1999 Impaired glucose tolerance in pregnant women with polycystic ovary syndrome. Obstet Gynecol 94:194–197[Abstract/Free Full Text]
  65. Diamant YZ, Rimon E, Evron S 1982 High incidence of preeclamptic toxemia in patients with polycystic ovarian disease. Eur J Obstet Gynecol Reprod Biol 14:199–204[CrossRef][Medline]
  66. de Vries MJ, Dekker GA, Schoemaker J 1998 Higher risk of preeclampsia in the polycystic ovary syndrome. A case control study. Eur J Obstet Gynecol Reprod Biol 76:91–95[CrossRef][Medline]
  67. Fridstrom M, Nisell H, Sjoblom P, Hillensjo T 1999 Are women with polycystic ovary syndrome at an increased risk of pregnancy-induced hypertension and/or preeclampsia? Hypertens Pregnancy 18:73–80[Medline]
  68. Kashyap S, Claman P 2000 Polycystic ovary disease and the risk of pregnancy-induced hypertension. J Reprod Med 45:991–994[Medline]
  69. Glueck CJ, Bornovali S, Pranikoff J, Goldenberg N, Dharashivkar S, Wang P 2004 Metformin, pre-eclampsia, and pregnancy outcomes in women with polycystic ovary syndrome. Diabet Med 21:829–836[CrossRef][Medline]
  70. Sagle M, Bishop K, Ridley N, Alexander FM, Michel M, Bonney RC, Beard RW, Franks S 1988 Recurrent early miscarriage and polycystic ovaries. BMJ 297:1027–1028[Medline]
  71. Homburg R, Armar NA, Eshel A, Adams J, Jacobs HS 1988 Influence of serum luteinising hormone concentrations on ovulation, conception, and early pregnancy loss in polycystic ovary syndrome. BMJ 297:1024–1026[Medline]
  72. Balen AH, Tan SL, MacDougall J, Jacobs HS 1993 Miscarriage rates following in vitro fertilization are increased in women with polycystic ovaries and reduced by pituitary desensitization with buserelin. Hum Reprod 8:959–964[Abstract/Free Full Text]
  73. Watson H, Kiddy DS, Hamilton-Fairley D, Scanlon MJ, Barnard C, Collins WP, Bonney RC, Franks S 1993 Hypersecretion of luteinizing hormone and ovarian steroids in women with recurrent early miscarriage. Hum Reprod 8:829–833[Abstract/Free Full Text]
  74. Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Roberts KA, Nestler JE 2002 Effects of metformin on early pregnancy loss in the polycystic ovary syndrome. J Clin Endocrinol Metab 87:524–529[Abstract/Free Full Text]
  75. Regan L, Owen EJ, Jacobs HS 1990 Hypersecretion of luteinising hormone, infertility, and miscarriage. Lancet 336:1141–1144[CrossRef][Medline]
  76. Legro RS, Kunselman AR, Dodson WC, Dunaif A 1999 Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab 84:165–169[Abstract/Free Full Text]
  77. Hernan WH, Brandle M, Zhang P, Williamson DF, Matulik MJ, Ratner RE, Lachin JM, Engelgau MM 2003 Costs associated with the primary prevention of type 2 diabetes mellitus in the diabetes prevention program. Diabetes Care 26:36–47[Abstract/Free Full Text]
  78. American Heart Association 2004 Heart disease and stroke statistics: 2004 update. Dallas: American Heart Association
  79. Talbott EO, Zborowski JV, Sutton-Tyrrell K, McHugh-Pemu KP, Guzick DS 2001 Cardiovascular risk in women with polycystic ovary syndrome. Obstet Gynecol Clin North Am 28:111–133, vii[CrossRef][Medline]
  80. Dahlgren E, Janson PO, Johansson S, Lapidus L, Oden A 1992 Polycystic ovary syndrome and risk for myocardial infarction. Evaluated from a risk factor model based on a prospective population study of women. Acta Obstet Gynecol Scand 71:599–604[Medline]
  81. Sukalich S, Guzick D 2003 Cardiovascular health in women with polycystic ovary syndrome. Semin Reprod Med 21:309–315[CrossRef][Medline]
  82. Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, Speizer FE, Manson JE 2002 Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab 87:2013–2017[Abstract/Free Full Text]
  83. Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS 2004 Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab 89:5454–5461[Abstract/Free Full Text]
  84. Orio Jr F, Palomba S, Spinelli L, Cascella T, Tauchmanova L, Zullo F, Lombardi G, Colao A 2004 The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab 89:3696–3701[Abstract/Free Full Text]
  85. Tarkun I, Arslan BC, Canturk Z, Turemen E, Sahin T, Duman C 2004 Endothelial dysfunction in young women with polycystic ovary syndrome: relationship with insulin resistance and low-grade chronic inflammation. J Clin Endocrinol Metab 89:5592–5596[Abstract/Free Full Text]
  86. Elting MW, Korsen TJ, Bezemer PD, Schoemaker J 2001 Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod 16:556–560[Abstract/Free Full Text]
  87. Pierpoint T, McKeigue PM, Isaacs AJ, Wild SH, Jacobs HS 1998 Mortality of women with polycystic ovary syndrome at long-term follow-up. J Clin Epidemiol 51:581–586[CrossRef][Medline]
  88. Guyatt G, Weaver B, Cronin L, Dooley JA, Azziz R 2004 Health-related quality of life in women with polycystic ovary syndrome, a self-administered questionnaire, was validated. J Clin Epidemiol 57:1279–1287[CrossRef][Medline]
  89. Sonino N, Fava GA, Mani E, Belluardo P, Boscaro M 1993 Quality of life of hirsute women. Postgrad Med J 69:186–189[Abstract]
  90. Sanchez LA, Perez M, Azziz R 2002 Laser hair reduction in the hirsute patient: a critical assessment. Hum Reprod Update 8:169–181[Abstract/Free Full Text]
  91. Futterweit W, Dunaif A, Yeh HC, Kingsley P 1988 The prevalence of hyperandrogenism in 109 consecutive female patients with diffuse alopecia. J Am Acad Dermatol 19:831–836[Medline]
  92. O’Driscoll JB, Mamtora H, Higginson J, Pollock A, Kane J, Anderson DC 1994 A prospective study of the prevalence of clear-cut endocrine disorders and polycystic ovaries in 350 patients presenting with hirsutism or androgenic alopecia. Clin Endocrinol (Oxf) 41:231–236[Medline]
  93. Cela E, Robertson C, Rush K, Kousta E, White DM, Wilson H, Lyons G, Kingsley P, McCarthy MI, Franks S 2003 Prevalence of polycystic ovaries in women with androgenic alopecia. Eur J Endocrinol 149:439–442[Abstract]
  94. Dawson KG, Gomes D, Gerstein H, Blanchard JF, Kahler KH 2002 The economic cost of diabetes in Canada, 1998. Diabetes Care 25:1303–1307[Abstract/Free Full Text]
  95. Leigh JP, McCurdy SA, Schenker MB 2001 Costs of occupational injuries in agriculture. Public Health Rep 116:235–248[Medline]
  96. Goodarzi MO, Quinones MJ, Yang H, Azziz R, Rotter JI, Hsueh WA, The prevalence of polycystic ovary syndrome in Mexican American women. Fertil Steril, in press
  97. Dumesic DA, Herrmann RR, O’Brien AM 1997 Estimated prevalence of undiagnosed glucose intolerance from hyperandrogenic anovulation among women requesting electrolysis. Int J Fertil Womens Med 42:255–260[Medline]
  98. Farah L, Lazenby AJ, Boots LR, Azziz R 1999 Prevalence of polycystic ovary syndrome in women seeking treatment from community electrologists. Alabama Professional Electrology Association Study Group. J Reprod Med 44:870–874[Medline]



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