Given all its systemic adaptive requirements, pregnancy shares several features with physical exercise. In this pilot study, we aimed to assess the physiological response to submaximal cardiopulmonary exercise testing (CPET) in early pregnancy. In 20 healthy, pregnant women (<13 weeks gestation) and 20 healthy, non‐pregnant women, we performed a CPET with stationary cycling during a RAMP protocol until 70% of the estimated maximum heart rate (HR) of each participant. Hemodynamic and respiratory parameters were non‐invasively monitored by impedance cardiography (PhysioFlow®) and a breath‐by‐breath analyzer (OxyconTM). To compare both groups, we used linear regression analysis, adjusted for age. We observed a similar response of stroke volume, cardiac output (CO) and HR to stationary cycling in pregnant and non‐pregnant women, but a slightly lower 1‐min recovery rate of CO (−3.9 [−5.5;‐2.3] vs. −6.6 [−8.2;‐5.1] L min−1 min−1; p = .058) and HR (−38 [−47; −28] vs. −53 [−62; −44] bpm/min; p = .065) in pregnant women. We also observed a larger increase in ventilation before the ventilatory threshold (+6.2 [5.4; 7.0] vs. +3.2 [2.4; 3.9] L min−1 min−1; p < .001), lower PETCO2 values at the ventilatory threshold (33 [31; 34] vs. 36 [34; 38] mmHg; p = .042) and a larger increase of breathing frequency after the ventilatory threshold (+4.6 [2.8; 6.4] vs. +0.6 [−1.1; 2.3] breaths min−1 min−1; p = .015) in pregnant women. In conclusion, we observed a slower hemodynamic recovery and an increased ventilatory response to exercise in early pregnancy.
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Understanding the cardiovascular disease (CVD) risk for women with polycystic ovary syndrome (PCOS) at reproductive age is crucial. To investigate this, we compared the cardiometabolic profiles of different PCOS groups over a median interval of 15.8 years. The study focused on three groups: (1) women with PCOS who were hyperandrogenic at both initial and follow-up screening (HA-HA), (2) those who transitioned from hyperandrogenic to normoandrogenic (HA-NA), and (3) those who remained normoandrogenic (NA-NA). At initial and follow-up screenings, both HA-HA and HA-NA groups showed higher body mass indexes compared to the NA-NA group. Additionally, at follow-up, the HA-HA and HA-NA groups exhibited higher blood pressure, a higher prevalence of hypertension, elevated serum triglycerides and insulin levels, and lower levels of HDL cholesterol compared to the NA-NA group. Even after adjusting for BMI, significant differences persisted in HDL cholesterol levels and hypertension prevalence among the groups (HA-HA: 53.8%, HA-NA: 53.1%, NA-NA: 14.3%, p < 0.01). However, calcium scores and the prevalence of coronary plaques on CT scans were similar across all groups. In conclusion, women with PCOS and hyperandrogenism during their reproductive years exhibited an unfavorable cardiometabolic profile during their post-reproductive years, even if they changed to a normoandrogenic status.
Study question Does unsupervised clustering identify biologically distinct subtypes in a cohort of women with polycystic ovary syndrome (PCOS) diagnosed by Rotterdam criteria? Summary answer This study demonstrates that unsupervised hierarchical clustering of eight pre-defined quantitative reproductive and metabolic traits identifies biologically distinct subtypes in women with PCOS. What is known already PCOS is a common, heterogeneous, endocrine disorder in women of reproductive-age. PCOS diagnosed by NIH or non-NIH Rotterdam criteria or by self-report is generally genetically similar. Using Hierarchical Clustering (HC), we have previously identified discrete, stable PCOS subtypes, which we designated reproductive (higher LH, FSH, SHBG) and metabolic (higher BMI, insulin, glucose), in a United States cohort of ∼900 PCOS women diagnosed by NIH criteria (Dapas et al. PLoS Med, 2020). The cases that did not cluster were designated “background subtype”. The subtypes appeared to capture biologically meaningful differences because they were associated with distinct and novel genome-wide significant loci. Study design, size, duration In the current study, we applied HC to the same traits (BMI, LH, FSH, DHEAS, SHBG, testosterone, fasting insulin and fasting glucose). We then assessed whether additional traits differed between the subtypes thus identified: anti-Müllerian hormone (AMH), total follicle count, modified Ferriman-Gallwey score, estrogen, TSH, DHEA, cortisol, androstenedione, prolactin, LDL, HDL, triglycerides and cholesterol. Participants/materials, setting, methods Women of European ancestry, aged 13-45 years, n = 2502, with PCOS according to the Rotterdam criteria were included; n = 1067 also fulfilled NIH criteria. All quantitative traits were log-transformed to approximate a normal distribution. Z-scores were used to compare the differences between the three clusters using ANCOVA, corrected for age. Pair-wise comparison of the different clusters was performed using Fisher’s least significance difference method and adjusted for multiple testing. Main results and the role of chance We replicated discrete subtypes in this large cohort of women with PCOS defined by the Rotterdam criteria. There were 1026 cases in the metabolic subtype, 450 cases in the reproductive subtype and 1026 in the background subtype. Cases in the reproductive subtype had significantly (all P < 0.001) higher serum AMH levels, follicle counts and HDL levels compared to the metabolic and background subtypes. These findings suggest that the reproductive subtype captures affected women with the alterations in folliculogenesis characteristic of PCOS, without using PCOM to define this subtype. In contrast, the cases in the metabolic subtype had significantly (all P < 0.001) higher triglyceride and LDL levels compared to the other subtypes providing further evidence that this subtype identifies cases with cardiometabolic risk. Androstenedione and TSH levels were significantly increased in the metabolic subtype compared to the background subtype (P < 0.001) and to both subtypes (P = 0.004), respectively. Cortisol and prolactin levels did not differ among the three subtypes. All results did not differ when the analysis was limited to NIH PCOS cases. Overall, our findings suggest that these PCOS subtypes have different etiologies and clinical outcomes. Subtyping may enable precision medicine approaches to the management of what is currently classified as PCOS. Limitations, reasons for caution A limitation of the study is that we have not replicated these findings in an independent cohort. We have not used an orthogonal method, such as genome-wide association, to confirm that the subtypes capture biologically distinct groups. Wider implications of the findings Taken together with our previous studies suggesting that the genetic architecture of these subtypes differs, the current study implies that PCOS consists of several etiologically distinct disorders. Our findings provide an example of the power of modern disease classification based on objective biologic differences rather than expert opinion. Trial registration number Not applicable
PCOS (polycystic ovary syndrome) is associated with overweight and obesity. Women with PCOS and overweight or obesity present with more pronounced reproductive derangements. Moreover, when pregnant, pregnancy complications such as gestational diabetes, hypertensive disorders and preterm birth seem to be more prevalent in this population. The present study is a one-year randomized controlled trial to investigate the effect of a three-component (cognitive behavioral therapy, healthy diet and physical therapy) lifestyle intervention (LSI) with or without Short Message Service (SMS) on pregnancy leading to live birth, pregnancy complications and outcomes within 24 months after the start of the lifestyle intervention compared to care as usual (CAU). We hypothesized that pre-pregnancy weight loss and the adoption of a healthy lifestyle would cause more pregnancies, shorter time to conception and less pregnancy complications. Women diagnosed with PCOS according to the Rotterdam 2003 criteria and a BMI above 25 kg/m2 were included. A total of 183 participants were randomly assigned to three groups: 1) three-component lifestyle intervention with SMS (LSI SMS+); 2) three-component lifestyle intervention without SMS (LSI SMS-); 3) care as usual (CAU): encourage to lose weight autonomously (control group). Pregnancy and neonatal outcomes were collected from the Dutch Bureau of Statistics (CBS) combined with the Dutch Perinatal registry (Perined). Within 24 months after the start of the intervention the pregnancy rate leading to live birth was 41.7% (25/60) within SMS+, 38.1% (24/63) within SMS- and 38.3% (23/60) within CAU. This was non-significant between the groups. Mean time to pregnancy for SMS+ was 18.3 months, 19.1 months for SMS- and 19.4 months for CAU (p=0.775). Gestational diabetes (LSI: 8.2% vs CAU: 21.7%, p=0.133), hypertensive disorders (LSI: 8.2% vs CAU: 13.0%, p=0.673) and preterm birth (LSI: 12.2% vs CAU: 17.4%, p=0.716) rates were all lower in the LSI groups (SMS+ and SMS- combined) compared to CAU. This trial demonstrated a non-significant positive trend in pregnancy outcomes in favor of the lifestyle intervention groups. We believe that a pre-pregnancy three-component lifestyle intervention in overweight or obese women with PCOS supports the attempts to get a healthy pregnancy by creating weight loss with positive effects on their physical and mental health. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.
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