Marie Louise Misso

Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis

BACKGROUND Polycystic ovary syndrome (PCOS) is a common condition in reproductive-aged women associated with impaired glucose tolerance (IGT), type 2 diabetes mellitus (DM2) and the metabolic syndrome. METHODS A literature search was conducted (MEDLINE, CINAHL, EMBASE, clinical trial registries and hand-searching) identifying studies reporting prevalence or incidence of IGT, DM2 or metabolic syndrome in women with and without PCOS. Data were presented as odds ratio (OR) [95% confidence interval (CI)] with fixed- and random-effects meta-analysis by Mantel-Haenszel methods. Quality testing was based on Newcastle-Ottawa Scaling and The Cochrane Collaborations risk of bias assessment tool. Literature searching, data abstraction and quality appraisal were performed by two investigators. RESULTS A total of 2192 studies were reviewed and 35 were selected for final analysis. Women with PCOS had increased prevalence of IGT (OR 2.48, 95% CI 1.63, 3.77; BMI-matched studies OR 2.54, 95% CI 1.44, 4.47), DM2 (OR 4.43, 95% CI 4.06, 4.82; BMI-matched studies OR 4.00, 95% CI 1.97, 8.10) and metabolic syndrome (OR 2.88, 95% CI 2.40, 3.45; BMI-matched studies OR 2.20, 95% CI 1.36, 3.56). One study assessed IGT/DM2 incidence and reported no significant differences in DM2 incidence (OR 2.07, 95% CI 0.68, 6.30). One study assessed conversion from normal glucose tolerance to IGT/DM2 (OR 2.4, 95% CI 0.7, 8.0). No studies reported metabolic syndrome incidence. CONCLUSIONS Women with PCOS had an elevated prevalence of IGT, DM2 and metabolic syndrome in both BMI and non-BMI-matched studies. Few studies have determined IGT/DM2 or metabolic syndrome incidence in women with and without PCOS and further research is required.

Assessment and management of polycystic ovary syndrome: summary of an evidence-based guideline.

Helena J Teede, Marie L Misso, Amanda A Deeks, Lisa J Moran, Bronwyn G A Stuckey, Jennifer L A Wong, Robert J Norman and Michael F Costello on behalf of the Guideline Development Groups

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Dietary composition in the treatment of polycystic ovary syndrome: a systematic review to inform evidence-based guidelines

While lifestyle management is recommended as first-line treatment of polycystic ovary syndrome (PCOS), the optimal dietary composition is unclear. The aim of this study was to compare the effect of different diet compositions on anthropometric, reproductive, metabolic, and psychological outcomes in PCOS. A literature search was conducted (Australasian Medical Index, CINAHL, EMBASE, Medline, PsycInfo, and EBM reviews; most recent search was performed January 19, 2012). Inclusion criteria were women with PCOS not taking anti-obesity medications and all weight-loss or maintenance diets comparing different dietary compositions. Studies were assessed for risk of bias. A total of 4,154 articles were retrieved and six articles from five studies met the a priori selection criteria, with 137 women included. A meta-analysis was not performed due to clinical heterogeneity for factors including participants, dietary intervention composition, duration, and outcomes. There were subtle differences between diets, with greater weight loss for a monounsaturated fat-enriched diet; improved menstrual regularity for a low-glycemic index diet; increased free androgen index for a high-carbohydrate diet; greater reductions in insulin resistance, fibrinogen, total, and high-density lipoprotein cholesterol for a low-carbohydrate or low-glycemic index diet; improved quality of life for a low-glycemic index diet; and improved depression and self-esteem for a high-protein diet. Weight loss improved the presentation of PCOS regardless of dietary composition in the majority of studies. Weight loss should be targeted in all overweight women with PCOS through reducing caloric intake in the setting of adequate nutritional intake and healthy food choices irrespective of diet composition.

Association of gestational weight gain with maternal and infant outcomes: A systematic review and meta-analysis

Importance Body mass index (BMI) and gestational weight gain are increasing globally. In 2009, the Institute of Medicine (IOM) provided specific recommendations regarding the ideal gestational weight gain. However, the association between gestational weight gain consistent with theIOM guidelines and pregnancy outcomes is unclear. Objective To perform a systematic review, meta-analysis, and metaregression to evaluate associations between gestational weight gain above or below the IOM guidelines (gain of 12.5-18 kg for underweight women [BMI <18.5]; 11.5-16 kg for normal-weight women [BMI 18.5-24.9]; 7-11 kg for overweight women [BMI 25-29.9]; and 5-9 kg for obese women [BMI ≥30]) and maternal and infant outcomes. Data Sources and Study Selection Search of EMBASE, Evidence-Based Medicine Reviews, MEDLINE, and MEDLINE In-Process between January 1, 1999, and February 7, 2017, for observational studies stratified by prepregnancy BMI category and total gestational weight gain. Data Extraction and Synthesis Data were extracted by 2 independent reviewers. Odds ratios (ORs) and absolute risk differences (ARDs) per live birth were calculated using a random-effects model based on a subset of studies with available data. Main Outcomes and Measures Primary outcomes were small for gestational age (SGA), preterm birth, and large for gestational age (LGA). Secondary outcomes were macrosomia, cesarean delivery, and gestational diabetes mellitus. Results Of 5354 identified studies, 23 (n = 1 309 136 women) met inclusion criteria. Gestational weight gain was below or above guidelines in 23% and 47% of pregnancies, respectively. Gestational weight gain below the recommendations was associated with higher risk of SGA (OR, 1.53 [95% CI, 1.44-1.64]; ARD, 5% [95% CI, 4%-6%]) and preterm birth (OR, 1.70 [1.32-2.20]; ARD, 5% [3%-8%]) and lower risk of LGA (OR, 0.59 [0.55-0.64]; ARD, −2% [−10% to −6%]) and macrosomia (OR, 0.60 [0.52-0.68]; ARD, −2% [−3% to −1%]); cesarean delivery showed no significant difference (OR, 0.98 [0.96-1.02]; ARD, 0% [−2% to 1%]). Gestational weight gain above the recommendations was associated with lower risk of SGA (OR, 0.66 [0.63-0.69]; ARD, −3%; [−4% to −2%]) and preterm birth (OR, 0.77 [0.69-0.86]; ARD, −2% [−2% to −1%]) and higher risk of LGA (OR, 1.85 [1.76-1.95]; ARD, 4% [2%-5%]), macrosomia (OR, 1.95 [1.79-2.11]; ARD, 6% [4%-9%]), and cesarean delivery (OR, 1.30 [1.25-1.35]; ARD, 4% [3%-6%]). Gestational diabetes mellitus could not be evaluated because of the nature of available data. Conclusions and Relevance In this systematic review and meta-analysis of more than 1 million pregnant women, 47% had gestational weight gain greater than IOM recommendations and 23% had gestational weight gain less than IOM recommendations. Gestational weight gain greater than or less than guideline recommendations, compared with weight gain within recommended levels, was associated with higher risk of adverse maternal and infant outcomes.

Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis

BACKGROUND Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. METHODS Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle ± placebo. RESULTS Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, -0.32, P = 0.0005) and subcutaneous adipose tissue (MD -92.49 cm(2), 95% CI -164.14, -20.84, P = 0.01) and increased number of menstrual cycles (MD 1.06, 95% CI 0.30, 1.82, P = 0.006) after 6 months compared with lifestyle ± placebo. There were no differences in other anthropometric, metabolic (surrogate markers of insulin resistance, fasting and area under the curve glucose, lipids and blood pressure), reproductive (clinical and biochemical hyperandrogenism), and psychological (quality of life) outcomes after 6 months between lifestyle + metformin compared with lifestyle ± placebo. With metformin alone compared with lifestyle ± placebo, weight and BMI were similar after 6 months, but testosterone was lower with metformin. CONCLUSIONS Lifestyle + metformin is associated with lower BMI and subcutaneous adipose tissue and improved menstruation in women with PCOS compared with lifestyle ± placebo over 6 months. Metformin alone compared with lifestyle showed similar BMI at 6 months. These results suggest the combination of lifestyle with metformin has a role to play in weight management: a key concern for women with PCOS. Existing study limitations include small sample sizes, short durations and risk of bias. With international guidelines now acknowledging that lifestyle and pharmacotherapy are required for weight loss and maintenance in obesity, future studies of appropriate size and duration are vital to clarify the role of metformin in PCOS management.

Adipose aromatase gene expression is greater in older women and is unaffected by postmenopausal estrogen therapy

Objective: Although natural menopause is associated with loss of ovarian estrogen production, this life phase is followed by a significant increase in estrogen-related cancers, namely breast and endometrial cancer. These tissues, as well as adipose, skeletal, and vascular tissues and the brain are important sites of postmenopausal estrogen production. Circulating C19 steroid precursors are essential substrates for extragonadal estrogen synthesis; however, the levels of these androgenic precursors decline markedly with advancing age. This implies an increase in capacity for extragonadal tissues to produce estrogen with age. Design: To explore this, and the effects of the menopause transition and postmenopausal estrogen therapy on extragonadal estrogen biosynthesis, we have compared the expression of the aromatase gene and estrogen (ER) and androgen receptors (AR) in subcutaneous abdominal and gluteal fat taken from premenopausal (group 1: n = 11), postmenopausal (group 2: n = 10), and postmenopausal women taking estrogen therapy (group 3: n = 10). All subjects were of normal body mass index, euglycemic, and normolipemic. Results: The postmenopausal women were older (group 1, 43.1 ± 5.0 vs groups 2 and 3, 57.9 ± 7.4 years, P < 0.001 and 56.1 ± 4.5 years, P < 0.001, respectively) and had lower serum estradiol levels (group 2, 22.2 ± 3.2 vs group 1, 442.5 ± 248.2 pmol/L, P < 0.05), which were restored to premenopausal levels with estrogen therapy. Expression analysis revealed that levels of transcripts encoding aromatase were greater in gluteal than abdominal depots in each group in postmenopausal versus premenopausal women (P < 0.05). Use of hormone therapy did not influence aromatase gene expression in either depot. No differences were detected in the expression of ER or AR between groups of between tissue depots. Conclusion: Thus, the capacity of adipose tissue to produce estrogen seems to increase significantly with age at the time of menopause and to be unaltered by exogenous estrogen therapy. This difference in extragonadal estrogen production with age may play a pivotal role in the increase in estrogen-dependent malignancies in the postmenopausal years.

Aromatase inhibitors for PCOS: a systematic review and meta-analysis

BACKGROUND The effectiveness of aromatase inhibitors (AIs) in the treatment of anovulatory polycystic ovary syndrome (PCOS) remains unclear. The objective was to determine whether AIs are effective in improving fertility outcomes in women with PCOS. METHODS Databases were searched until July 2011. Inclusion criteria were women with PCOS, who are infertile, receiving any type, dose and frequency of AI compared with placebo, no other treatment or other infertility treatment. Outcomes were rates of: ovulation, pregnancy, live birth, multiple pregnancies, miscarriage and adverse events, as well as quality of life and cost effectiveness. Data were extracted and risk of bias was assessed. A random-effects model was used for the meta-analyses, using odds ratios (ORs) and rate ratios (RRs). RESULTS The search returned 4981 articles, 78 articles addressed AIs and 13 randomized controlled trials (RCTs) met the inclusion criteria. No RCTs compared AIs versus placebo or no treatment, in therapy naïve women with PCOS. Meta-analyses of six RCTs comparing letrozole with clompihene citrate (CC) demonstrated that letrozole improved the ovulation rate per patient [OR 2.90 (95% confidence interval (CI) 1.72, 4.88), I(2) = 0%, P < 0.0001]; however, there was no statistical difference for the ovulation rate per cycle or the pregnancy, live birth, multiple pregnancy or miscarriage rates. Letrozole also did not improve pregnancy or live birth rates compared with placebo or with CC plus metoformin in women with CC-resistant PCOS. Results of comparisons of letrozole and anastrozole in women with CC-resistant PCOS were conflicting in terms of ovulation and pregnancy rates. CONCLUSIONS In the absence of supportive high-quality evidence, AIs should not be recommended as the first-line pharmacological therapy for infertility in women with PCOS, and further research is needed.

Metformin versus clomiphene citrate for infertility in non-obese women with polycystic ovary syndrome: a systematic review and meta-analysis

UNLABELLED BACKGROUND Recent studies suggest that metformin may be more effective in women with polycystic ovary syndrome (PCOS) who are non-obese. The objective here is to determine and compare the effectiveness of metformin and clomiphene citrate for improving fertility outcomes in women with PCOS and a BMI < 32 kg/m(2) (BMI 32 kg/m(2) was used to allow for international differences in BMI values which determine access to infertility therapy through the public health system). METHODS Databases were searched for English language articles until July 2011. INCLUSION CRITERIA women of any age, ethnicity and weight with PCOS diagnosed by all current criteria, who are infertile; at least 1000 mg of any type of metformin at any frequency, including slow release and standard release, compared with any type, dose and frequency of clomiphene citrate. OUTCOMES rates of ovulation, live birth, pregnancy, multiple pregnancies, miscarriage, adverse events, quality of life and cost effectiveness. Data were extracted and risk of bias assessed. A random effects model was used for meta-analyses of data, using risk ratios (relative risk). RESULTS The search returned 4981 articles, 580 articles addressed metformin or clomiphene citrate and four randomized controlled trials (RCTs) comparing metformin with clomiphene citrate were included. Upon meta-analysis of the four RCTs, we were unable to detect a statistically significant difference between the two interventions for any outcome in women with PCOS and a BMI < 32 kg/m(2), owing to significant heterogeneity across the RCTs. CONCLUSIONS Owing to conflicting findings and heterogeneity across the included RCTs, there is insufficient evidence to establish a difference between metformin and clomiphene citrate in terms of ovulation, pregnancy, live birth, miscarriage and multiple pregnancy rates in women with PCOS and a BMI < 32 kg/m(2). However, a lack of superiority of one treatment is not evidence for equivalence, and further methodologically rigorous trials are required to determine whether there is a difference in effectiveness between metformin and placebo (or no treatment) or between metformin and clomiphene citrate for ovulation induction in women with PCOS who are non-obese. Until then, caution should be exercised when prescribing metformin as first line pharmacological therapy in this group of women.

The treatment of infertility in polycystic ovary syndrome: a brief update

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility. Lifestyle change alone is considered the first‐line treatment for the management of infertile anovulatory PCOS women who are overweight or obese. First‐line medical ovulation induction therapy to improve fertility outcomes is clomiphene citrate, whilst gonadotrophins, laparoscopic ovarian surgery or possibly metformin are second line in clomiphene citrate‐resistant PCOS women. There is currently insufficient evidence to recommend aromatase inhibitors over that of clomiphene citrate in infertile anovulatory PCOS women in general or specifically in therapy naive or clomiphene citrate‐resistant PCOS women. IVF/ICSI treatment is recommended either as a third‐line treatment or in the presence of other infertility factors.