Christy M. Stetter

Benefit of Delayed Fertility Therapy With Preconception Weight Loss Over Immediate Therapy in Obese Women With PCOS

CONTEXT In overweight/obese women with polycystic ovary syndrome (PCOS), the relative benefit of delaying infertility treatment to lose weight vs seeking immediate treatment is unknown. OBJECTIVE We compared the results of two, multicenter, concurrent clinical trials treating infertility in women with PCOS. DESIGN, SETTING, AND PARTICIPANTS This was a secondary analysis of two randomized trials conducted at academic health centers studying women 18-40 years of age who were overweight/obese and infertile with PCOS. INTERVENTION We compared immediate treatment with clomiphene from the Pregnancy in Polycystic Ovary Syndrome II (PPCOS II) trial (N = 187) to delayed treatment with clomiphene after preconception treatment with continuous oral contraceptives, lifestyle modification (Lifestyle: including caloric restriction, antiobesity medication, behavioral modification, and exercise) or the combination of both (combined) from the Treatment of Hyperandrogenism Versus Insulin Resistance in Infertile Polycystic Ovary Syndrome (OWL PCOS) trial (N = 142). MAIN OUTCOME MEASURES Live birth, pregnancy loss, and ovulation were measured. RESULTS In PPCOS II, after four cycles of clomiphene, the cumulative per-cycle ovulation rate was 44.7% (277/619) and the cumulative live birth rate was 10.2% (19/187), nearly identical to that after oral contraceptive pretreatment in the OWL PCOS trial (ovulation 45% [67/149] and live birth: 8.5% [4/47]). In comparison, deferred clomiphene treatment preceded by lifestyle and combined treatment in OWL PCOS offered a significantly better cumulative ovulation rate compared to immediate treatment with clomiphene. (Lifestyle: 62.0% [80/129]; risk ratio compared to PPCOS II = 1.4; 95% confidence interval [CI], 1.1-1.7; P = .003; combined: 64.3% [83/129]; risk ratio compared to PPCOS II = 1.4; 95% CI, 1.2-1.8; P < .001 and a significantly better live birth rate lifestyle: 25.0% [12/48]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.7; P = .01 and combined: 25.5% [12/47]; risk ratio compared to PPCOS II = 2.5; 95% CI, 1.3-4.8; P = .01). CONCLUSIONS These data show the benefit of improved ovulation and live birth with delayed infertility treatment with clomiphene citrate when preceded by lifestyle modification with weight loss compared with immediate treatment. Pretreatment with oral contraceptives likely has little effect on the ovulation and live birth rate compared with immediate treatment.

Effects of atorvastatin on vascular function, inflammation, and androgens in women with polycystic ovary syndrome: a double-blind, randomized, placebo-controlled trial.

To determine the effects of statins on vascular function, inflammation, and androgen levels in women with polycystic ovary syndrome (PCOS), we randomized 20 women with PCOS who had low-density lipoprotein cholesterol levels >100 mg/dL to atorvastatin (40 mg/day) or placebo for 6 weeks and found that atorvastatin reduced androgen levels, biomarkers of inflammation, and blood pressure; increased insulin levels and brachial artery conductance during reactive hyperemia; and failed to improve brachial artery flow-mediated dilation. We conclude that until additional studies demonstrate a clear risk-to-benefit ratio favoring statin therapy in PCOS, statins should only be used in women with PCOS who meet current indications for statin treatment.

High-dose vitamin D supplementation and measures of insulin sensitivity in polycystic ovary syndrome: a randomized, controlled pilot trial

OBJECTIVE To determine the effects of high-dose vitamin D on insulin sensitivity in polycystic ovary syndrome (PCOS). DESIGN Randomized, placebo-controlled trial. SETTING Academic medical center. PATIENT(S) Twenty-eight women with PCOS. INTERVENTION(S) Vitamin D3, 12,000 IU, or placebo daily for 12 weeks. MAIN OUTCOME MEASURE(S) The primary outcome was quantitative insulin sensitivity check index. Secondary outcomes included glucose and insulin levels during a 75-g oral glucose tolerance test and blood pressure. RESULT(S) Twenty-two women completed the study. Compared with placebo, vitamin D significantly increased 25-hydroxyvitamin D (mean [95% confidence interval] in vitamin D group 20.1 [15.7 to 24.5] ng/mL at baseline and 65.7 [52.3 to 79.2] ng/mL at 12 weeks; placebo 22.5 [18.1 to 26.8] ng/mL at baseline and 23.8 [10.4 to 37.2] ng/mL at 12 weeks). There were no significant differences in quantitative insulin sensitivity check index and other measures of insulin sensitivity; however, we observed trends toward lower 2-hour insulin and lower 2-hour glucose. We also observed a protective effect of vitamin D on blood pressure. CONCLUSION(S) In women with PCOS, insulin sensitivity was unchanged with high-dose vitamin D, but there was a trend toward decreased 2-hour insulin and a protective effect on blood pressure. CLINICAL TRIAL REGISTRATION NUMBER NCT00907153.

Weight Loss and Lowering Androgens Predict Improvements in Health-Related Quality of Life in Women With PCOS

CONTEXT Polycystic ovary syndrome (PCOS) is associated with reduced health-related quality of life (HRQOL) and increased prevalence of depressive and anxiety disorders. The impact of PCOS-specific treatments on these co-morbidities is unclear. OBJECTIVE To assess the impact of weight loss and decreasing hyperandrogenism on HRQOL and mood and anxiety disorders in women with PCOS. DESIGN/SETTING/PARTICIPANTS A secondary analysis of a randomized controlled trial (OWL-PCOS) of preconception treatment conducted at two academic centers in women (age, 18-40 years; body mass index, 27-42 kg/m(2)) with PCOS defined by Rotterdam criteria. INTERVENTION Continuous oral contraceptive pill (OCP) or intensive lifestyle intervention or the combination (Combined) for 16 weeks. MAIN OUTCOME MEASURE(S) Changes in HRQOL assessed by PCOSQ and SF-36 and prevalence of depression and anxiety disorder assessed by PRIME-MD PHQ. RESULTS The lowest scores were noted on the general health domain of the SF-36 and the weight and infertility domains on the PCOSQ. All three interventions resulted in significant improvement in the general health score on the SF-36. Both the OCP and Combined groups showed improvements in all domains of the PCOSQ (P < .01) compared to baseline scores. The Combined group had significant improvements in the weight, body hair, and infertility domains compared to a single treatment group (P < .05). In a linear regression model, change in weight correlated with improvements in the weight domain (P < .001) and physical well-being (P < .02), change in T correlated with improvements in the hair domain (P < .001), and change in both weight and T correlated with the infertility (P < .001) and menstrual domains (P < .05). CONCLUSIONS Both weight loss and OCP use result in significant improvements in several physical and mental domains related to quality of life, depressive symptoms, and anxiety disorders, and combined therapies offer further benefits in overweight/obese women with PCOS.

Normal Pubertal Development in Daughters of Women with PCOS: A Controlled Study

Context Daughters of women with polycystic ovary syndrome (PCOS) are thought to be at increased risk for developing stigmata of the syndrome, but the ontogeny during puberty is uncertain. Objective We phenotyped daughters (n = 76) of mothers with PCOS and daughters (n = 80) from control mothers for reproductive and metabolic parameters characteristic of PCOS. Design, Setting, and Participants We performed a matched case/control study at Penn State Hershey Medical Center that included non-Hispanic, white girls 4 to 17 years old. Intervention We obtained birth history, biometric, ovarian ultrasounds, whole-body dual-energy X-ray absorptiometry scan for body composition, 2-hour glucose challenged salivary insulin levels, and two timed urinary collections (12 hours overnight and 3 hours in the morning) for gonadotropins and sex steroids. Main Outcome Measures We measured integrated urinary levels of adrenal (dehydroepiandrosterone sulfate) and ovarian [testosterone (TT)] steroids. Other endpoints included integrated salivary insulin levels and urinary luteinizing hormone levels. Results There were no differences in detection rates or mean levels for gonadotropins and sex steroids in timed urinary collections between PCOS daughters and control daughters, nor were there differences in integrated salivary insulin levels. Results showed that 69% of Tanner 4/5 PCOS daughters vs 31% of control daughters had hirsutism defined as a Ferriman-Gallwey score >8 (P = 0.04). There were no differences in body composition as determined by dual-energy X-ray absorptiometry between groups in the three major body contents (i.e., bone, lean body mass, and fat) or in ovarian volume between groups. Conclusions Matched for pubertal stage, PCOS daughters have similar levels of urinary androgens and gonadotropins as well as glucose-challenged salivary insulin levels.

Mindfulness-based stress reduction for overweight/obese women with and without polycystic ovary syndrome: Design and methods of a pilot randomized controlled trial ☆

Mindfulness-based stress reduction (MBSR) may be beneficial for overweight/obese women, including women with polycystic ovary syndrome (PCOS), as it has been shown to reduce psychological distress and improve quality of life in other patient populations. Preliminary studies suggest that MBSR may also have salutary effects on blood pressure and blood glucose. This paper describes the design and methods of an ongoing pilot randomized controlled trial evaluating the feasibility and effects of MBSR in PCOS and non-PCOS women who are overweight or obese. Eighty six (86) women with body mass index ≥25 kg/m2, including 31 women with PCOS, have been randomized to 8 weeks of MBSR or health education control, and followed for 16 weeks. The primary outcome is mindfulness assessed with the Toronto Mindfulness Scale. Secondary outcomes include measures of blood pressure, blood glucose, quality of life, anxiety and depression. Our overall hypothesis is that MBSR will increase mindfulness and ultimately lead to favorable changes in blood pressure, blood glucose, psychological distress and quality of life in PCOS and non-PCOS women. This would support the integration of MBSR with conventional medical treatments to reduce psychological distress, cardiovascular disease and diabetes in PCOS and non-PCOS women who are overweight or obese.

Health knowledge among the millennial generation

The Millennial Generation, also known as Generation Y, is the demographic cohort following Generation X, and is generally regarded to be composed of those individuals born between 1980 and 2000. They are the first to grow up in an environment where health-related information is widely available by internet, TV and other electronic media, yet we know very little about the scope of their health knowledge. This study was undertaken to quantify two domains of clinically relevant health knowledge: factual content and ability to solve health related questions (application) in nine clinically related medical areas. Study subjects correctly answered, on average, 75% of health application questions but only 54% of health content questions. Since students were better able to correctly answer questions dealing with applications compared to those on factual content contemporary US high school students may not use traditional hierarchical learning models in acquisition of their health knowledge.

Susceptibility MRI captures nigral pathology in patients with parkinsonian syndromes: R2* and QSM Reflect Pathology in Parkinsonism

Background: Parkinsonisms are neurodegenerative disorders characterized pathologically by α‐synuclein‐positive (e.g., PD, diffuse Lewy body disease, and MSA) and/or tau‐positive (e.g., PSP, cortical basal degeneration) pathology. Using R2* and quantitative susceptibility mapping, susceptibility changes have been reported in the midbrain of living parkinsonian patients, although the exact underlying pathology of these alterations is unknown.

Individually Tailored, Adaptive Intervention to Manage Gestational Weight Gain: Protocol for a Randomized Controlled Trial in Women With Overweight and Obesity

Background High gestational weight gain is a major public health concern as it independently predicts adverse maternal and infant outcomes. Past interventions have had only limited success in effectively managing pregnancy weight gain, especially among women with overweight and obesity. Well-designed interventions are needed that take an individualized approach and target unique barriers to promote healthy weight gain. Objective The primary aim of the study is to describe the study protocol for Healthy Mom Zone, an individually tailored, adaptive intervention for managing weight in pregnant women with overweight and obesity. Methods The Healthy Mom Zone Intervention, based on theories of planned behavior and self-regulation and a model of energy balance, includes components (eg, education, self-monitoring, physical activity/healthy eating behaviors) that are adapted over the intervention (ie, increase in intensity) to better regulate weight gain. Decision rules inform when to adapt the intervention. In this randomized controlled trial, women are randomized to the intervention or standard care control group. The intervention is delivered from approximately 8-36 weeks gestation and includes step-ups in dosages (ie, Step-up 1 = education + physical activity + healthy eating active learning [cooking/recipes]; Step-up 2 = Step-up 1 + portion size, physical activity; Step-up 3 = Step-up 1 + 2 + grocery store feedback, physical activity); 5 maximum adaptations. Study measures are obtained at pre- and postintervention as well as daily (eg, weight), weekly (eg, energy intake/expenditure), and monthly (eg, psychological) over the study period. Analyses will include linear mixed-effects models, generalized estimating equations, and dynamical modeling to understand between-group and within-individual effects of the intervention on weight gain. Results Recruitment of 31 pregnant women with overweight and obesity has occurred from January 2016 through July 2017. Baseline data have been collected for all participants. To date, 24 participants have completed the intervention and postintervention follow-up assessments, 3 are currently in progress, 1 dropped out, and 3 women had early miscarriages and are no longer active in the study. Of the 24 participants, 13 women have completed the intervention to date, of which 1 (8%, 1/13) received only the baseline intervention, 3 (23%, 3/13) received baseline + step-up 1, 6 (46%, 6/13) received baseline + step-up 1 + step-up 2, and 3 (23%, 3/13) received baseline + step-up 1 + step-up 2 +step-up 3. Data analysis is still ongoing through spring 2018. Conclusions This is one of the first intervention studies to use an individually tailored, adaptive design to manage weight gain in pregnancy. Results from this study will be useful in designing a larger randomized trial to examine efficacy of this intervention and developing strategies for clinical application. Registered Report Identifier RR1-10.2196/9220

Lateralized Basal Ganglia Vulnerability to Pesticide Exposure in Asymptomatic Agricultural Workers

Pesticide exposure is linked to Parkinsons disease, a neurodegenerative disorder marked by dopamine cell loss in the substantia nigra of the basal ganglia (BG) that often presents asymmetrically. We previously reported that pesticide-exposed agricultural workers (AW) have nigral diffusion tensor imaging (DTI) changes. The current study sought to confirm this finding, and explore its hemisphere and regional specificity within BG structures using an independent sample population. Pesticide exposure history, standard neurological exam, high-resolution magnetic resonance imaging (T1/T2-weighted and DTI), and [123I]ioflupane SPECT images (to quantify striatal dopamine transporters) were obtained from 20 AW with chronic pesticide exposure and 11 controls. Based on median cumulative days of pesticide exposure, AW were subdivided into high (AWHi, n = 10) and low (AWLo, n = 10) exposure groups. BG (nigra, putamen, caudate, and globus pallidus [GP]) fractional anisotropy (FA), mean diffusivity (MD), and striatal [123I]ioflupane binding in each hemisphere were quantified, and compared across exposure groups using analysis of variance. Left, but not right, nigral and GP FA were significantly lower in AW compared with controls (ps < .029). None of the striatal (putamen and caudate) DTI or [123I]ioflupane binding measurements differed between AW and controls. Subgroup analyses indicated that significant left nigral and GP DTI changes were present only in the AWHi (p ≤ .037) but not the AWLo subgroup. AW, especially those with higher pesticide exposure history, demonstrate lateralized microstructural changes in the nigra and GP, whereas striatal areas appear relatively unaffected. Future studies should elucidate how environmental toxicants cause differential lateralized- and regionally specific brain vulnerability.