Rogerio A. Lobo

Assessment of Cardiovascular Risk and Prevention of Cardiovascular Disease in Women with the Polycystic Ovary Syndrome: A Consensus Statement by the Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society

OBJECTIVE Women with polycystic ovary syndrome (PCOS) often have cardiovascular disease (CVD) risk factors. The Androgen Excess and Polycystic Ovary Syndrome (AE-PCOS) Society created a panel to provide evidence-based reviews of studies assessing PCOS-CVD risk relationships and to develop guidelines for preventing CVD. PARTICIPANTS An expert panel in PCOS and CVD reviewed literature and presented recommendations. EVIDENCE Only studies comparing PCOS with control patients were included. All electronic databases were searched; reviews included individual studies/databases, systematic reviews, abstracts, and expert data. Articles were excluded if other hyperandrogenic disorders were not excluded, PCOS diagnosis was unclear, controls were not described, or methodology precluded evaluation. Inclusion/exclusion criteria were confirmed by at least two reviewers and arbitrated by a third. CONSENSUS PROCESS Systematic reviews of CVD risk factors were compiled and submitted for approval to the AE-PCOS Society Board. CONCLUSIONS Women with PCOS with obesity, cigarette smoking, dyslipidemia, hypertension, impaired glucose tolerance, and subclinical vascular disease are at risk, whereas those with metabolic syndrome and/or type 2 diabetes mellitus are at high risk for CVD. Body mass index, waist circumference, serum lipid/glucose, and blood pressure determinations are recommended for all women with PCOS, as is oral glucose tolerance testing in those with obesity, advanced age, personal history of gestational diabetes, or family history of type 2 diabetes mellitus. Mood disorder assessment is suggested in all PCOS patients. Lifestyle management is recommended for primary CVD prevention, targeting low-density and non-high-density lipoprotein cholesterol and adding insulin-sensitizing and other drugs if dyslipidemia or other risk factors persist.

Consensus on infertility treatment related to polycystic ovary syndrome

The treatment of infertile women with polycystic ovary syndrome (PCOS) is surrounded by many controversies. This paper describes, on the basis of the currently available evidence, the consensus reached by a group of experts regarding the therapeutic challenges raised in these women. Before any intervention is initiated, preconceptional counselling should be provided emphasizing the importance of life style, especially weight reduction and exercise in overweight women, smoking and alcohol consumption. The recommended first-line treatment for ovulation induction remains the anti-estrogen clomiphene citrate (CC). Recommended second-line intervention, should CC fail to result in pregnancy, is either exogenous gonadotrophins or laparoscopic ovarian surgery (LOS). The use of exogenous gonadotrophins is associated with increased chances for multiple pregnancy and, therefore, intense monitoring of ovarian response is required. LOS alone is usually effective in <50% of women and additional ovulation induction medication is required under those circumstances. Overall, ovulation induction (representing the CC, gonadotrophin paradigm) is reported to be highly effective with a cumulative singleton live birth rate of 72%. Recommended third-line treatment is in vitro fertilization. More patient-tailored approaches should be developed for ovulation induction based on initial screening characteristics of women with PCOS. Such approaches may result in deviation from the above mentioned first-, second- or third-line ovulation strategies in well-defined subsets of patients. Metformin use in PCOS should be restricted to women with glucose intolerance. Based on recent data available in the literature, the routine use of this drug in ovulation induction is not recommended. Insufficient evidence is currently available to recommend the clinical use of aromatase inhibitors for routine ovulation induction. Even singleton pregnancies in PCOS are associated with increased health risk for both the mother and the fetus.

The Importance of Diagnosing the Polycystic Ovary Syndrome

Hyperandrogenism and insulin were linked as early as 1921, when Achard and Thiers (1) published their classic description of a bearded women with diabetes (1). Since then, researchers have realized that most women with hyperandrogenism show evidence of a disorder known as the polycystic ovary syndrome (PCOS), which is extremely common but heterogeneous. Most women with PCOS have some degree of insulin resistance, although it may be subtle. Abnormalities of insulin secretion and action have been implicated in the pathophysiology of PCOS. For this and other reasons, diagnosis of PCOS is important. The polycystic ovary syndrome, then called the SteinLeventhal syndrome, was first described in 1935. Originally, diagnosis required pathognomonic ovarian findings and the clinical triad of hirsutism, amenorrhea, and obesity (2). The next diagnostic milestone occurred 30 years later, when researchers in the late 1960s and early 1970s noted derangements in the hypothalamicpituitary axis. This focused the diagnosis on endocrine criteria, such as elevated levels of serum luteinizing hormone or ratio of luteinizing hormone to follicle-stimulating hormone (3, 4). With the advent of pelvic ultrasonography in the 1970s and 1980s (first, abdominal sonography and, later, vaginal sonography), the recognition of a characteristic polycystic ovary complicated the diagnosis. Some believed that ultrasonographic findings alone were sufficient to make a diagnosis. In this setting, it was misleading to call the disorder polycystic ovary (PCO) or polycystic ovarian disease (PCOD) because these terms completely ignored the well-accepted endocrine features. It was also quickly realized that polycystic ovaries can occur in some normal women and in women with well-defined endocrinopathies as varied as hypothalamic amenorrhea and congenital abnormal hyperplasia (5, 6). In normal ovulatory women with no other typical endocrine features, we prefer to call this finding as polycystic-appearing ovary (7) to distinguish it from the term PCO, which is often used synonymously, but incorrectly, with PCOS. The polycystic ovarian syndrome is extremely prevalent and is considered the most frequently encountered endocrinopathic condition. It has been suggested that the disorder occurs in 4% to 7% of women of reproductive age (8, 9). During the reproductive years, PCOS is associated with important reproductive morbidity, including infertility, abnormal bleeding, increased pregnancy loss, and complications of pregnancy (10). Because women with PCOS also have an increased risk for endometrial carcinoma because of long-standing unopposed estrogen stimulation, their menstrual function must be continually monitored (11). In 1990, the National Institutes of Health formed a group to investigate PCOS. No consensus was reached regarding the naming of the disorder (12). However, in women who present with hyperandrogenism and chronic anovulation, a diagnosis of PCOS is considered reasonable after other endocrine disorders (for example, congenital adrenal enzymatic deficiencies and tumors) have been ruled out. Hyperandrogenism and chronic anovulation remain the two most characteristic clinical features of the disorder and are discussed separately. Criteria for the diagnosis of PCOS are presented in the Table. Table. Criteria for Clinical Diagnosis of the Polycystic Ovary Syndrome Hyperandrogenism Hyperandrogenism is a key feature of PCOS. Although the adrenal gland may contribute, hyperandrogenism is principally ovarian in origin among women with a primary diagnosis of PCOS. In various populations around the world (13), it has been found that most women with PCOS have elevated levels of serum androgens; however, normal levels may be found in some women. For a diagnosis of PCOS, it is sufficient to have elevated serum androgen levels or a biological expression of hyperandrogenism (acne or hirsutism). Serum testosterone level is the best marker for ovarian hyperandrogenism, and dehydroepiandrosterone sulfate is the best adrenal marker. It is recommended that these analytes be measured. The measurement of free testosterone provides a higher diagnostic yield for ovarian hyperandrogenism because levels of sex-hormone binding globulin are decreased. However, clinical assays used to test this measure vary considerably, affecting its reliability. It is important to point out that hyperandrogenemia is not synonymous with hirsutism or acne. Some ethnic groups (for example, Asians) have substantial hyperandrogenism (elevated levels of testosterone and dehydroepiandrosterone sulfate) without any significant skin manifestations (13, 14). Anovulation Anovulation in PCOS is usually chronic and presents as oligomenorrhea or amenorrhea of perimenarchial onset. Nevertheless, a history of regular menses is also possible. Because the degree and chronicity of self-reported menstrual irregularity vary, it has been the most difficult aspect of the diagnosis to define. Some women who report normal menses may be anovulatory. In a recent prospective survey of hyperandrogenic women who reported normal menses, we found that 21% experienced anovulation despite reporting regular menstrual cycles (15). It is important to note, however, that PCOS is extremely heterogeneous and that a small number of affected women may have ovulatory function. Although this contradicts our definition of PCOS, it is now accepted that a subset of women with the syndrome who have typical polycystic ovaries on ultrasonography also experience ovulation. The Ovarian Diagnosis The polycystic ovary is easily diagnosed. It is enlarged, usually greater than 9 mL with more than 8 mL peripherally oriented cystic structures (<10 mm) in a sonographic plane surrounded by an increased stromal mass (>25% of the ovarian volume) (16). However, although we and others have insisted on these strict criteria, a sonographic spectrum exists. Polycystic ovaries may sometimes be absent in women with all of the other classic clinical characteristics of PCOS. This may be related to the particular resolution of the ultrasonographic technique (for example, vaginal scans are much more sensitive than abdominal scans). We again emphasize that although the ultrasonographic diagnosis of polycystic ovaries is most common in women with PCOS, it may occur in women with other disorders and in healthy women. Ultrasonographic diagnosis alone is not sufficient to diagnose PCOS. Test for Gonadotropin-Releasing Hormone Agonists Some investigators believe that PCOS can be diagnosed by performing a test for gonadotropin-releasing hormone agonists and demonstrating an exaggerated ovarian response (17). This test is helpful because it can show that the ovary is producing more androgen in response to luteinizing hormone, but it is our view that it should be considered an adjunctive test. It is not specific enough to pinpoint the diagnosis, and it is impractical to perform. Insulin Resistance Many of the late complications of PCOS seem to be related to insulin resistance (18). Burghen and coworkers (19) first reported this observation in 1980, and we and many other groups later confirmed it (20, 21). Although severe insulin resistance, which is often associated with acanthosis nigricans (22), may be present in PCOS, most patients have only a mild form with slightly elevated fasting serum insulin levels. A ratio of fasting glucose to insulin is usually sufficient to diagnose insulin resistance (23), although this ratio is not valid in patients with overt glucose intolerance. It has been suggested that with more sophisticated techniques (for example, an intravenous glucose tolerance test or clamps), insulin resistance may be diagnosed in almost all women with PCOS. Although insulin resistance is associated with obesity, it is also found in normal-weight women with PCOS (13, 21, 24) and in women with PCOS from different ethnic groups (13). It has been suggested that anovulation is a major determinant of insulin resistance in women with PCOS. We recently confirmed this and have found that although all women with PCOS may have evidence of insulin resistance, it is more pronounced in those with chronic anovulation than in those who have ovulatory cycles. The pathogenesis of insulin resistance remains unclear. However, it has been reported that insulin resistance may be related to excessive serine phosphorylation of the insulin receptor in at least 50% of women with PCOS (25). Dysfunction of cells may also occur in women with PCOS, making them susceptible to type 2 diabetes mellitus (26). More recently, it was suggested that women with PCOS exhibit decreased action of chiroinositol, which is important for insulin signaling. Some patients have been successfully treated with d-chiroinositol (27). Impaired Glucose Tolerance and Diabetes Because of insulin resistance, all women with PCOS have increased risk for impaired glucose tolerance and overt type 2 diabetes mellitus. A recent study found that 31% of obese, reproductive-age women with PCOS had impaired glucose tolerance and that 7.5% had overt diabetes (28). In addition, 10.3% of nonobese women with PCOS had impaired glucose tolerance and 1.5% had diabetes, a rate almost three times that of the general population (28). In another study, longitudinal follow-up of women who had been treated with wedge resection showed that 16% developed type 2 diabetes mellitus by menopause (29). These and other data (30) show that women with PCOS have a high risk for diabetes and that this risk is similar in different populations and ethnic groups (28). Because of the known long-term morbidity associated with diabetes, even young women with PCOS should be followed closely for impaired glucose tolerance and diabetes. In our view, women should be screened for glucose intolerance with an oral glucose tolerance test. We suggest that this be done in obese women with PCOS before pregnancy is attempted and in all affected women with PCOS after 40

Comparative effects of oral esterified estrogens with and without methyltestosterone on endocrine profiles and dimensions of sexual function in postmenopausal women with hypoactive sexual desire

OBJECTIVE In some women, a decline in sexual interest accompanies a relative androgen insufficiency after menopause. We sought to characterize the hormonal effects of the combination of oral esterified estrogens and methyltestosterone and to investigate whether this regimen improves hypoactive sexual desire. DESIGN Double-blind randomized trial. SETTING Healthy volunteers in a multicenter research environment. PATIENT(S) Postmenopausal women taking estrogen therapy who were experiencing hypoactive sexual desire. INTERVENTION(S) 4 months of treatment with 0.625 mg of esterified estrogens (n = 111) or the combination of 0.625 mg of esterified estrogens and 1.25 mg of methyltestosterone (n = 107). MAIN OUTCOME MEASURES Baseline and end-of-study measurements of total and bioavailable testosterone and sex hormone-binding globulin (SHBG), and mean change in level of sexual interest or desire as rated on the Sexual Interest Questionnaire. RESULT(S) Treatment with the combination of esterified estrogens and methyltestosterone significantly increased the concentration of bioavailable testosterone and suppressed SHBG. Scores measuring sexual interest or desire and frequency of desire increased from baseline with combination treatment and were significantly greater than those achieved with esterified estrogens alone. Treatment with the combination was well tolerated. CONCLUSION(S) Increased circulating levels of unbound testosterone and suppression of SHBG provide a plausible hormonal explanation for the significantly improved sexual functioning in women receiving the combination of esterified estrogen and methyltestosterone.

Metabolic syndrome after menopause and the role of hormones

OBJECTIVES The purpose of this review is to focus on the importance of metabolic syndrome (MBS) and its increased prevalence in postmenopausal (PM) women. Also the role of hormonal therapy in PM women with MBS will be discussed. METHODS Review of the relevant literature and results from recent clinical trials. RESULTS MBS may occur in 40% of PM women and is largely determined by overweight status and obesity. Weight gain, particularly an increase in central fat mass increases in PM women, beginning a few years prior to menopause. Hormonal Therapy (HT) in normal PM women, generally decreases abdominal fat, but the effect of transdermal estrogen is preferable to oral therapy in this regard. In women with MBS, oral therapy was found to increase leptin and the leptin/adiponectin ratio, while transdermal therapy showed no changes. HT has been found to improve insulin resistance in PM women, although the data are mixed. In women with MBS, oral therapy was found to worsen parameters of insulin resistance, while transdermal therapy had minimal effects overall. Women with MBS have elevations in several inflammation and coagulation factors. Both oral and transdermal HT reduce inflammation markers except for levels of CRP and MMP-9, which increase with oral therapy, but are unaffected by the transdermal route. Oral estrogen has a small pro-coagulant effect, not observed with transdermal therapy, in both normal PM women and those with MBS. The beneficial effects of HT on lipids occur in PM women with and without MBS, although the changes in the latter are minimal. Blood pressure was not affected by HT in women with MBS. CONCLUSIONS Weight gain and obesity largely drives the increased prevalence of MBS in PM women. Use of HT is beneficial overall for reducing many of the parameters of MBS. Our own data would suggest that in MBS, transdermal therapy may be preferable to oral therapy, at least in standard doses.

Evaluation of bazedoxifene/conjugated estrogens for the treatment of menopausal symptoms and effects on metabolic parameters and overall safety profile

OBJECTIVE To evaluate the effects of a tissue-selective estrogen complex (TSEC) composed of bazedoxifene/conjugated estrogens (BZA/CE) on menopausal symptoms, metabolic parameters, and overall safety. DESIGN Multicenter, double-blind, placebo- and active-controlled phase 3 trial (Selective estrogens, Menopause, And Response to Therapy [SMART]-1). SETTING Outpatient clinical. PATIENT(S) Healthy, postmenopausal women (n = 3,397) age 40 to 75 with an intact uterus. INTERVENTION(S) Single tablets of BZA (10, 20, or 40 mg), each with CE (0.625 or 0.45 mg); raloxifene 60 mg; or placebo taken daily for 2 years. MAIN OUTCOME MEASURE(S) Hot flushes, breast pain, vaginal atrophy, metabolic parameters, and adverse events. RESULT(S) BZA (20 mg)/CE (0.625 or 0.45 mg) significantly reduced the frequency and severity of hot flushes and improved measures of vaginal atrophy compared with placebo. At week 12, the daily number of hot flushes decreased by 51.7% to 85.7% with all BZA/CE doses vs. 17.1% for placebo. BZA/CE improved lipid parameters and homocysteine levels, did not significantly change carbohydrate metabolism, and had only minor effects on some coagulation parameters. The incidences of breast pain and adverse events were similar between BZA/CE and placebo. CONCLUSION The TSEC composed of BZA (20 mg)/CE (0.625 or 0.45 mg) is an effective and safe treatment for menopausal symptoms.

Addition of alendronate to ongoing hormone replacement therapy in the treatment of osteoporosis: a randomized, controlled clinical trial

Alendronate and estrogen are effective therapies for postmenopausal osteoporosis, but their efficacy and safety as combined therapy are unknown. The objective of this study was to evaluate the addition of alendronate to ongoing hormone replacement therapy (HRT) in the treatment of postmenopausal women with osteoporosis. A total of 428 postmenopausal women with osteoporosis, who had been receiving HRT for at least 1 yr, were randomized to receive either alendronate (10 mg/day) or placebo. HRT was continued in both groups. Changes in bone mineral density (BMD) and biochemical markers of bone turnover were assessed. Compared with HRT alone, at 12 months, alendronate plus HRT produced significantly greater increases in BMD of the lumbar spine (3.6% vs. 1.0%, P < 0.001) and hip trochanter (2.7% vs. 0.5%, P < 0.001); however, the between-group difference in BMD at the femoral neck was not significant (1.7% vs. 0.8%, P = 0.072). Biochemical markers of bone turnover (serum bone-specific alkaline phosphatase and urine N-telopeptide) decreased significantly at 6 and 12 months with alendronate plus HRT, and they remained within premenopausal levels. Addition of alendronate to ongoing HRT was generally well tolerated, with no significant between-group differences in upper gastrointestinal adverse events or fractures. This study demonstrated that, in postmenopausal women with low bone density despite ongoing treatment with estrogen, alendronate added to HRT significantly increased bone mass at both spine and hip trochanter and was generally well tolerated.

The diagnosis of polycystic ovary syndrome in adolescents

In women, the definition of polycystic ovary syndrome (PCOS) has become broad and includes several possible phenotypes. Because several features of PCOS may be in evolution in adolescents, we suggest that only firm criteria should be used to make a diagnosis of PCOS during adolescence. Hyperandrogenism, oligomenorrhea, and ovarian morphology change during adolescence and are discussed individually. Adolescents with incomplete criteria for a firm diagnosis of PCOS should be followed up carefully and may be diagnosed at a later time.

Postmenopausal hormone therapy: new questions and the case for new clinical trials

Observational studies suggest that postmenopausal hormone therapy (HT) prevents coronary heart disease, whereas randomized clinical trials have not confirmed a cardioprotective effect. Although observational studies may have overestimated the coronary benefit conferred by postmenopausal hormone use, there are other plausible explanations for the apparent discrepancy between previous results and the less favorable findings from clinical trials such as the large Womens Health Initiative. There is now a critical mass of data to support the hypothesis that age or time since menopause may importantly influence the benefit-risk ratio associated with HT, especially with respect to cardiovascular outcomes, and that the method of administration, dose, and formulation of exogenous hormones may also be relevant. Although the weight of the evidence indicates that older women and those with subclinical or overt coronary heart disease should not take HT, estrogen remains the most effective treatment currently available for vasomotor symptoms, and its effects on the development of coronary disease in newly postmenopausal women remain unclear. Moreover, effects of HT on quality of life and cognitive function in recently postmenopausal women merit further study. These unresolved clinical issues provide the rationale for the design of the Kronos Early Estrogen Prevention Study, a 5-year randomized trial that will evaluate the effectiveness of low-dose oral estrogen and transdermal estradiol in preventing progression of atherosclerosis in recently postmenopausal women.

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study.

Background Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. Methods and Findings KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. Conclusions The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. Trial Registration ClinicalTrials.gov NCT00154180 and NCT00623311