1 Department of Obstetrics and Gynecology, Pennsylvania State University College of Medicine, Hershey, PA and 2 Department of Obstetrics and Gynecology, Duke University, Durham, NC, USA
3 To whom correspondence should be addressed at: Department of Obstetrics and Gynecology, PO Box 850, 500 University Drive, M.S. Hershey Medical Center, Hershey, PA 17033, USA. Email: rsl1{at}psu.edu
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Abstract |
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Key words: diabetes prevention/hirsutism/hyperandrogenism/insulin resistance/pregnancy/randomized clinical trial/surrogate measure
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Introduction |
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PCOS is a heterogeneous disorder, one that has evolved over the years from a disease to a syndrome (note in the last decade the disappearance of the acronym PCOD and the phrase polycystic ovarian disease from the published literature). A disease suggests a more fully characterized set of symptoms than a syndrome, which is a looser association of symptoms. PCOS is a heterogeneous disorder, where current proposed diagnostic criteria include a number of disorders with similar phenotypes, but different aetiologies. However there is no single sign or symptom that is currently accepted as the sine qua non of the syndrome. Therefore, there is no gold standard test of this sign or symptom from which to determine the sensitivity/specificity of screening tests, entry criteria into a clinical trial or long-term sequelae.
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Potential diagnostic criteria in PCOS |
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Definition of surrogate end-points |
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Discussion of surrogate end-points |
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However, even such a well-validated surrogate variable can be misleading. For instance, in the Heart and Estrogen/Progestin Replacement Study trial, although combined hormone replacement therapy with continuous conjugated equine estrogens and medroxyprogesterone acetate resulted in favourable changes in the circulating lipid and lipoprotein levels in women with pre-existing heart disease, it was also associated with an increased cardiovascular event rate in the first year of the trial and no benefit in overall mortality over the course of the trial (Hulley et al., 1998). Similarly, increased cardiovascular events were seen in the Women's Health Initiative study of primary prevention of cardiovascular disease, despite favourable changes in lipid profiles with lowered levels of LDL cholesterol and elevated levels of HDL cholesterol in the treated groups (Writing Group for the Women's Health Initiative Investigators, 2002
; Manson et al., 2003
).
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Critique of surrogate end-points |
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In order to determine its location on the causal pathway, a full understanding of the aetiology of the disorder is necessary, as well as studies validating the relationship between the surrogate marker and the primary clinical outcome. A grading scheme of surrogate variables based on their validity has been proposed (Prentice, 1989). Given our incomplete understanding of the pathophysiology of PCOS, it is difficult to grade the location of any surrogate marker in its proximity to the unknown source of the disorder. Ideally, the best surrogate marker should predict the outcome of interest, both with and without the proposed intervention. Such a marker has to have been studied extensively with both natural history studies and randomized clinical trials, both of which are underrepresented in the PCOS literature. The consequences of using non-validated surrogate markers includes, in a best-case scenario, patient benefit, but in other scenarios they range from wasted resources and ambiguous results to frank patient harm (Holloway and Dick, 2002
).
A classic example of this latter scenario is the use of suppressing ventricular ectopic beats as a surrogate for reducing cardiovascular-related mortality after myocardial infarction (Anonymous, 1989). Because natural history studies showed that ventricular arrhythmias after a myocardial infarction increased the risk of subsequent death, it was hypothesized that if post-myocardial infarction arrhythmias were suppressed, then there would be a greater chance for survival. Eventually two new drugs, encainide and flecainide, were approved by the FDA on the basis of suppressing post-myocardial infarction arrhythmias. Their effect on the primary clinical end-point survival after a myocardial infarction was then evaluated in the Cardiac Arrhythmia Suppression Trial (CAST). This trial was terminated early because of excessive mortality in the flecainide and encainide treatment arms compared with the placebo arm of the trial. A similar lack of benefit to the post-myocardial patient were found with moricizine (Anonymous, 1992
) and lidocaine (Hine et al., 1989
; Holloway and Dick, 2002
).
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Surrogate end-points in PCOS |
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The subcategory of hyperandrogenemia within hyperandrogenism offers a number of potential circulating androgen markers, including testosterone, androstenedione, dihydrotestosterone, and even weak androgen precursors such as DHEA and DHEAS. There are no standardized commercial assays for measuring total levels of these hormones in the blood (Boots et al., 1998). Furthermore, because androgens circulate bound to various proteins and primarily to sex hormone-binding globulin (SHBG), there are a number of measures of circulating testosterone that attempt to measure the bioavailability of testosterone. These include assays for free testosterone usually by equilibrium dialysis, measures of the fraction of serum T not precipitated by 50% ammonium sulfate concentration (non-SHBG-T) (Tremblay and Dube, 1974
), and measures of circulating testosterone corrected for levels of SHBG and other proteins (i.e. albumin) like the free androgen index (Imani et al., 2000
). While these latter measures are felt to better reflect the clinical presentation than total testosterone levels (Vermeulen et al., 1999
), they have not been well validated in the realm of clinical trials.
Insulin sensitivity is another surrogate measure that is frequently investigated in clinical trials of women with PCOS. The gold standard test for determining insulin sensitivity (or at least insulin-mediated glucose uptake) is the euglycemic clamp, but this test is invasive, expensive and unwieldy for use in clinical practice (DeFronzo et al., 1979). Surrogate markers of insulin-mediated glucose uptake sensitivity are even more varied, and can rely on fasting measures of insulin and glucose as well as changes over time during dynamic challenges (Matsuda and DeFronzo, 1999
). In addition, a number of surrogate markers of the insulin resistance syndrome, such as plasminogen-activator inhibitor-1 (Velazquez et al., 1997
), C-reactive protein (Kelly et al., 2001
) and homocysteine (Yarali et al., 2001
), have been examined in women with PCOS. However, there are no universally accepted or validated markers of insulin resistance that have been recommended for use in clinical practice (American Diabetic Association, 1998
; Bloomgarden, 2003a
; b
).
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Critique of surrogate end-points in PCOS |
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|
However, ovulation should not be equated with pregnancy, as a host of other factors may affect both pregnancy and the true outcome of interest: a healthy live born infant (Figure 3). For example, in the published meta-analysis of metformin in women with PCOS, the clinical pregnancy rate comparing metformin with placebo did not show evidence of benefit [odds ratio 2.76; 95% confidence interval (CI) 0.858.98; P=0.09; although it should be noted that in the trials comparing clomiphene with metformin compared with clomiphene alone, a significant pregnancy benefit was noted for clomiphene and metformin: odds ratio 4.40; 95% CI 1.969.85; Lord et al., 2003]. Factors both extrinsic (such as male factor, tubal factor or maternal age) and intrinsic to PCOS can affect the chance for pregnancy. These intrinsic factors include the quality of the PCOS oocyte (Ashkenazi et al., 1995
; Chian et al., 1999
), PCOS endometrial abnormalities that may affect implantation (Tuckerman et al., 2000
) or other factors that may lead to an increased miscarriage risk in women with PCOS (Sagle et al., 1988
; Rai et al., 2000
).
|
Another primary clinical outcome of interest, hirsutism, has been studied extensively in women with and without PCOS. It is interesting to note that in the largest clinical trial of women with PCOS (in which women were diagnosed on the basis of the NICHD recommended diagnostic criteria of unexplained hyperandrogenemic chronic anovulation; Zawadski and Dunaif, 1992),
50% of the women did not have clinically recognized hirustism (Azziz et al., 2001
). There is a lack of well-validated surrogate measures of hirsutism, and even uncertainty as to optimal methods for quantifying changes in hirsutism in response to treatment (Barth, 1996
). Hirsutism scores are notoriously subjective (Holdaway et al., 1985
), and even the most frequently utilized standard for hirsutism scores, the modified FerrimanGallwey score, relies partially on non-midline, non-androgen-dependent body hair to make the diagnosis (Hatch et al., 1981
). In PCOS, the ability to discriminate unwanted excess hair with a diffuse distribution (hypertrichosis) from unwanted excess hair in androgen-dependent locations (hirsutism) is important, since reduction in excess androgen would be unlikely to improve hypertrichosis.
For example, other scales have focused on midline hair (Lorenzo, 1970; Derksen et al., 1993
), and the best discrimination between a control population and a hirsute population has been found using the sum of the scores for four regions: upper lip, chin, lower abdomen and thighs (Derksen et al., 1993
). Interobserver coefficient of variation between two observers was good (Derksen et al., 1993
). Single site assessment of chin or lower abdomen has been found to be sensitive, but to have poor specificity in the larger population (positive predictive value in the general population of <60%) (Knochenhauer et al., 2000
).
Despite these caveats about the difficulty of assessing hirsutism, there are acceptable methods for achieving an FDA indication for treating hirsutism. The approval of eflornithine hydrochloride cream for the treatment of female hirsutism by the FDA was based on a physician's global assessment scale, evaluating facial hair 48 h after shaving on treatment compared with placebo (Hickman et al., 2001). The methodology of this scale involved both objective and subjective measures of hirsutism (Hickman et al., 2001
). This example provides inspiration for further investigation of medications that improve hirsutism in women with PCOS.
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Critique of other primary outcomes in women with PCOS |
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There are also diseases where there are neither surrogate markers nor evidence of increased risk of the disease in women with PCOS. An example of this is endometrial cancer, and its precursor, atypical endometrial hyperplasia. There is little epidemiological data to suggest that women with PCOS per se are at increased risk for developing endometrial cancer (Hardiman et al., 2003). Again, the majority of data linking women with PCOS to endometrial cancer are case reports or case series (Jackson and Dockerty, 1957
), or retrospective casecontrol studies identifying risk factors within the cases with endometrial cancer, such as chronic anovulation (Coulam et al., 1983
) or hirsutism (Dahlgren et al., 1991
) (i.e. chronic anovulation) as synonymous with PCOS. Thus, there is evidence that women with PCOS have risk factors for endometrial cancer (i.e. chronic anovulation, obesity and diabetes) without the firm epidemiological data supporting events.
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What are the feasible clinical end-points of interest in women with PCOS? |
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An intriguing area of further research would be a diabetes prevention trial in women with PCOS. There is a high prevalence of glucose intolerance (40%) in these women (Ehrmann et al., 1999
; Legro et al., 1999
), present even in adolescence (Palmert et al., 2002
), which is a strong modifiable risk factor for developing type 2 diabetes. Small studies in women with PCOS have shown high conversion rates to type 2 diabetes over time (Ehrmann et al., 1999
; Norman et al., 2001
). Further intervention trials, including both lifestyle and pharmaceutical interventions, have shown consistently a significant decline in the conversion to type 2 diabetes in women with impaired glucose tolerance (Chiasson et al., 1998
; Buchanan et al., 2002
; Knowler et al., 2002
). This is an outcome that may prove feasible in a future trial in women with PCOS (although it should be noted that even the development of type 2 diabetes is a surrogate end-pointthe true clinical end-points would be morbidity and mortality from complications of diabetes). As the above discussion suggests, the two clinical outcomes that appear most feasible as the end-point of a clinical trial are hirsutism and live birth.
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Conclusions |
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Acknowledgements |
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Submitted on February 3, 2004; accepted on April 22, 2004.