Ricardo Azziz

The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report.

OBJECTIVE To review all available data and recommend a definition for polycystic ovary syndrome (PCOS) based on published peer-reviewed data, whether already in use or not, to guide clinical diagnosis and future research. DESIGN Literature review and expert consensus. SETTING Professional society. PATIENTS None. INTERVENTION(S) None. MAIN OUTCOME MEASURE(S) A systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. RESULT(S) The Task Force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the Androgen Excess and PCOS (AE-PCOS) Society AE-PCOS Board of Directors. No section was finalized until all members were satisfied with the contents, and minority opinions noted. Statements were not included that were not supported by peer-reviewed evidence. CONCLUSION(S) Based on the available data, it is the view of the AE-PCOS Society Task Force that PCOS should be defined by the presence of hyperandrogenism (clinical and/or biochemical), ovarian dysfunction (oligo-anovulation and/or polycystic ovaries), and the exclusion of related disorders. However, a minority considered the possibility that there may be forms of PCOS without overt evidence of hyperandrogenism, but recognized that more data are required before validating this supposition. Finally, the Task Force recognized and fully expects that the definition of this syndrome will evolve over time to incorporate new research findings.

Polycystic ovary syndrome: etiology, pathogenesis and diagnosis

Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age, with a prevalence of up to 10%. Various diagnostic criteria have been proposed, generally centered around the features of hyperandrogenism and/or hyperandrogenemia, oligo-ovulation and polycystic ovarian morphology. Insulin resistance is present in a majority of cases, with compensatory hyperinsulinemia contributing to hyperandrogenism via stimulation of ovarian androgen secretion and inhibition of hepatic sex hormone-binding globulin production. Adipose tissue dysfunction has been implicated as a contributor to the insulin resistance observed in PCOS. Environmental and genetic factors also have a role in the development of PCOS. The syndrome is associated with numerous morbidities, including infertility, obstetrical complications, type 2 diabetes mellitus, cardiovascular disease, and mood and eating disorders. Despite these morbidities, PCOS may be common in our society owing to evolutionary advantages of the syndrome in ancient times, including smaller family sizes, reduced exposure to childbirth-related mortality, increased muscle mass and greater capacity to store energy. The diagnosis of PCOS hinges on establishing key features while ruling out other hyperandrogenic or oligo-ovulatory disorders. Treatment is focused on the goals of ameliorating hyperandrogenic symptoms, inducing ovulation and preventing cardiometabolic complications.

Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health--National Heart, Lung, and Blood Institute sponsored Women's Ischemia Syndrome Evaluation.

BACKGROUND Women with polycystic ovary syndrome (PCOS) have a greater clustering of cardiac risk factors. However, the link between PCOS and cardiovascular (CV) disease is incompletely described. OBJECTIVE The aim of this analysis was to evaluate the risk of CV events in 390 postmenopausal women enrolled in the National Institutes of Health-National Heart, Lung, and Blood Institute (NIH-NHLBI) sponsored Womens Ischemia Syndrome Evaluation (WISE) study according to clinical features of PCOS. METHODS A total of 104 women had clinical features of PCOS defined by a premenopausal history of irregular menses and current biochemical evidence of hyperandrogenemia. Hyperandrogenemia was defined as the top quartile of androstenedione (> or = 701 pg/ml), testosterone (> or = 30.9 ng/dl), or free testosterone (> or = 4.5 pg/ml). Cox proportional hazard model was fit to estimate CV death or myocardial infarction (n = 55). RESULTS Women with clinical features of PCOS were more often diabetic (P < 0.0001), obese (P = 0.005), had the metabolic syndrome (P < 0.0001), and had more angiographic coronary artery disease (CAD) (P = 0.04) compared to women without clinical features of PCOS. Cumulative 5-yr CV event-free survival was 78.9% for women with clinical features of PCOS (n = 104) vs. 88.7% for women without clinical features of PCOS (n = 286) (P = 0.006). PCOS remained a significant predictor (P < 0.01) in prognostic models including diabetes, waist circumference, hypertension, and angiographic CAD as covariates. CONCLUSION Among postmenopausal women evaluated for suspected ischemia, clinical features of PCOS are associated with more angiographic CAD and worsening CV event-free survival. Identification of postmenopausal women with clinical features of PCOS may provide an opportunity for risk factor intervention for the prevention of CAD and CV events.

Insulin resistance, polycystic ovary syndrome, and type 2 diabetes mellitus

OBJECTIVE To review the definition and prevalence of two insulin resistance (IR)-associated phenotypes, polycystic ovary syndrome (PCOS) and type 2 diabetes mellitus, as well as the risk and nature of their simultaneous presentation. DESIGN Review of published literature. RESULT(S) Insulin resistance affects between 10% and 25% of the general population. Two common disorders frequently associated with IR are PCOS, affecting 4% to 6% of reproductive-aged women, and type 2 diabetes mellitus, which is observed in about 2% to 6% of similarly aged women. Overall, about 50% to 70% of women with PCOS and 80% to 100% of patients with type 2 diabetes mellitus have variable degrees of IR. Insulin resistance and its secondary hyperinsulinemia appear to underlie many of the endocrine features of PCOS in a large proportion of such patients. The risk of type 2 diabetes mellitus among PCOS patients is 5- to 10-fold higher than normal. In turn, the risk of PCOS among reproductive-aged type 2 diabetes mellitus patients appears to be similarly increased. CONCLUSION(S) It remains to be determined whether PCOS and type 2 diabetes mellitus represent no more than different clinical manifestations of the same IR syndrome, with their phenotypic differences due to the presence or absence of a coincidental genetic defect at the level of the ovary or pancreas, respectively, or representing the result of etiologically different subtypes of IR syndromes.

Prevalence of polycystic ovary syndrome (PCOS) in first-degree relatives of patients with PCOS

OBJECTIVE To determine the rate of clinically evident polycystic ovary syndrome (PCOS) among first-degree female relatives within families with a proband affected by PCOS. DESIGN Clinical and biochemical evaluation of the mothers and sisters of 93 patients with PCOS. The diagnosis of PCOS was established by: [1] a history of oligomenorrhea, [2] clinical evidence (i.e., hirsutism) or biochemical evidence (i.e., elevated total or free T) of hyperandrogenism, and [3] the exclusion of related disorders. SETTING Tertiary care university. PATIENT(S) Patients with PCOS and their mothers and sisters. INTERVENTION(S) Interview, physical examination, and hormonal testing on blood samples were performed for all subjects. MAIN OUTCOME MEASURE(S) The presence of hirsutism and hyperandrogenemia was determined in the mothers and sisters of the patients with PCOS. RESULT(S) Of the 78 mothers and 50 sisters evaluated clinically, 19 (24%) and 16 (32%) were affected with PCOS, respectively. A higher rate of PCOS was observed when only premenopausal women not taking hormones (i.e., untreated) were considered (i.e., 35% of mothers and 40% of sisters), consistent with amelioration of symptoms with hormonal therapy or aging. These rates of PCOS are significantly higher than that observed in our general population (approximately 4%) and suggest the involvement of a major genetic component in the disorder. CONCLUSION(S) The rates of PCOS in mothers and sisters of patients with PCOS were 24% and 32%, respectively, although the risk was higher when considering untreated premenopausal women only.

Screening for 21-hydroxylase–deficient nonclassic adrenal hyperplasia among hyperandrogenic women: a prospective study

OBJECTIVE To prospectively establish the specificity, sensitivity, and positive predictive value (PPV) of a basal 17-hydroxyprogesterone (17-HP) level for the screening of 21-hydroxylase-deficient nonclassic adrenal hyperplasia (NCAH) among hyperandrogenic women. DESIGN Prospective observational trial. SETTING Tertiary care academic medical centers. PATIENT(S) Eight healthy controls, 20 patients with NCAH, and 284 consecutively seen patients with hyperandrogenism. INTERVENTION(S) All controls and patients with NCAH, and select patients with hyperandrogenism, underwent acute ACTH (1-24) stimulation. MAIN OUTCOME MEASURE(S) Specificity was determined by measuring 17-HP every other day during one menstrual cycle in 8 healthy women with normal ovulation (107 samples). Sensitivity was determined by measuring 17-HP between 7 and 9 A.M. and 3 and 5 P.M. on the same day in 20 patients with genetically confirmed NCAH. The PPV was determined by prospectively measuring 17-HP in 284 consecutively seen hyperandrogenic women at their initial evaluation. The diagnosis of NCAH was established by a stimulated 17-HP level of >10 ng/mL. RESULT(S) Among controls, 17-HP levels of <2, <3, and <4 ng/mL all had a specificity of 100% when obtained in the follicular phase; when obtained in the luteal phase, they had specificities of 53%, 82%, and 82%, respectively. Among patients with NCAH, 17-HP levels of >2, >3, and >4 ng/mL had sensitivities of 100%, 90%, and 90%, respectively, for the detection of the disorder when obtained in the morning, and sensitivities of 95%, 90%, and 85%, respectively, when obtained in the afternoon. Among the 284 consecutively seen hyperandrogenic women, the PPVs of the first and second 17-HP levels were 7.3% and 19% for a cutoff level of >2 ng/mL, 13% and 43% for a cutoff level of >3 ng/mL, and 33% and 40% for a cutoff level of >4 ng/mL, respectively. CONCLUSION(S) A basal 17-HP level is a useful screening tool for NCAH. A cutoff level of 4 ng/mL has maximum specificity and PPV, with little loss in sensitivity if testing is performed in the morning and during the follicular phase. However, a lower cutoff level (e.g., 2 or 3 ng/mL) is preferable if testing is performed at odd hours of the day, as is common in many practices, and maximum sensitivity is desired.

Prevalence of adrenal androgen excess in patients with the polycystic ovary syndrome (PCOS)

Objective  To determine the prevalence of adrenal androgen (AA) excess in the polycystic ovary syndrome (PCOS) using age‐ and race‐specific normative values.

Androgen excess disorders in women

Normal androgen physiology clinical manifestations of androgen excess inherited causes of androgen excess - the adrenal hyperplasias inherited causes of androgen excess - severe insulin resistant hyperandrogenic syndromes the polycystic ovary syndrome.

Visually scoring hirsutism

BACKGROUND Hirsutism is the presence of excess body or facial terminal (coarse) hair growth in females in a male-like pattern, affects 5-15% of women, and is an important sign of underlying androgen excess. Different methods are available for the assessment of hair growth in women. METHODS We conducted a literature search and analyzed the published studies that reported methods for the assessment of hair growth. We review the basic physiology of hair growth, the development of methods for visually quantifying hair growth, the comparison of these methods with objective measurements of hair growth, how hirsutism may be defined using a visual scoring method, the influence of race and ethnicity on hirsutism, and the impact of hirsutism in diagnosing androgen excess and polycystic ovary syndrome. RESULTS Objective methods for the assessment of hair growth including photographic evaluations and microscopic measurements are available but these techniques have limitations for clinical use, including a significant degree of complexity and a high cost. Alternatively, methods for visually scoring or quantifying the amount of terminal body and facial hair growth have been in use since the early 1920s; these methods are semi-quantitative at best and subject to significant inter-observer variability. The most common visual method of scoring the extent of body and facial terminal hair growth in use today is based on a modification of the method originally described by Ferriman and Gallwey in 1961 (i.e. the mFG method). CONCLUSION Overall, the mFG scoring method is a useful visual instrument for assessing excess terminal hair growth, and the presence of hirsutism, in women.

Measurement of total serum testosterone levels using commercially available kits : high degree of between-kit variability

OBJECTIVE The measurement of total serum testosterone has an established clinical role in the management of male hypogonadism and female androgen excess disorders. We studied the between-kit variability and precision of six different commercially available testosterone assays and compared them with an established in-house method. DESIGN Laboratory observational prospective study. SETTING Tertiary university medical center clinical laboratory. PATIENT(S) Three groups of samples each of men (n = 36) and women (n = 15) who had high, normal, or low levels of sex hormone-binding globulin (SHBG), respectively, were studied. INTERVENTION(S) Individual and pooled (male and female) serum samples were analyzed for total testosterone concentration using six different commercially available assays and one in-house method. MAIN OUTCOME MEASURE(S) The between-kit variability and the effect of the mean (+/- SD) SHBG level were determined, the results obtained with the use of the kits and the in-house method were compared, and the intraassay variability (i.e., precision) was evaluated. RESULT(S) Male samples demonstrated a 26.3%-40.8% variance in the results obtained with different kits, which was greatest for samples with the lowest SHBG levels. For female samples, between-kit variability ranged from 57%-115% (average, 77%). The percent deviation of the results obtained with the use of commercial methods from those obtained with the use of our in-house assay was greater for men (mean variance, 194%) than for women (mean variance, 67%). The female pool intraassay coefficient of variation was 3.8% with the use of the in-house method and ranged from 8.9%-21.2% with the use of the commercial kits. The male pool intraassay coefficient of variation was 3.1% with the use of the in-house method and ranged from 3.3%-5.5% with the use of the commercial kits. CONCLUSION(S) Most commercially available kits for measuring the total serum testosterone level demonstrated significant between-kit variability, which was greatest for female samples. Further, samples with the lowest SHBG levels had the highest between-kit variances. These data strongly suggest that the measurement of total serum testosterone using commercial kits may have limited utility, particularly for the detection of hyperandrogenemia.