Objectives: Polycystic ovary syndrome (PCOS) is associated with an increased cardiometabolic risk that might not necessarily translate into adverse cardiovascular outcome later in life. Recently, alterations in gut microbial composition have been reported in the syndrome. Microbiota-dependent metabolite trimethylamine N-oxide (TMAO) and its precursors are closely linked with development of atherosclerotic cardiovascular disease, independently of traditional risk factors. We aimed to assess whether TMAO and its precursors are altered in PCOS and to determine potential impact of treatment on these metabolites.
Design: Prospective study.Patients: Twenty-seven overweight/obese patients with PCOS and 25 age-and BMImatched healthy control women.Measurements: At baseline, fasting serum TMAO and its precursors were measured after a 3-day standardized diet. Patients received 3-month OC therapy along with general dietary advice after which all measurements were repeated.
Results: Patients had higher total testosterone (T) and free androgen index (FAI)whereas whole-body fat mass, fasting plasma glucose, insulin and lipids were similar between the groups. PCOS group showed significantly higher serum levels of TMAO and its precursors; choline, betaine and carnitine. TMAO and choline showed correlations with T. After 3 months of OC use, TMAO and its precursors significantly decreased along with reductions in BMI, T and FAI.
Conclusions:This study reports for the first time that TMAO and its precursors are elevated in PCOS which might contribute to increased cardiometabolic risk of the syndrome and that short-term OC use along with lifestyle intervention is associated with reduction of these microbiome-dependent metabolites.
K E Y W O R D Scardiometabolic risk, microbiome, oral contraceptives, polycystic ovary syndrome, trimethylamine N-oxide | 811 EYUPOGLU Et aL.
Inconsistencies have been reported on the effect of sex on aldosterone levels leading to clinical confusion. The reasons for these inconsistencies, are uncertain but include: estrogen and/or its receptor modulating target gene responses to mineralocorticoid receptor activation and aldosterone secretagogues’ levels. This study’s goal was to determine whether aldosterone’s biosynthesis also differed by sex. Two approaches were used. First, plasma renin activity (PRA) and aldosterone were measured in rats. Both were significantly higher in males. Secondly, using rat zona glomerulosa (ZG) cells, we assessed three ex-vivo areas:1) activity/levels of early steps in aldosterone’s biosynthesis (StAR and CYP11A1); 2) activity/levels of a late step (CYP11B2); and 3) the status of the MR mediated, ultrashort-feedback-loop. Females had higher expression of CYP11A1 and StAR; and increased CYP11A1 activity (increased pregnenolone/ corticosterone levels) but did not differ in CYP11B2 expression or activity (aldosterone/ levels). Activating the ZG’s MR (thereby activating the ultrashort-feedback-loop) reduced CYP11B2’s activity similarly in both sexes. Ex-vivo, these molecular effects were accompanied, in females, by lower aldosterone basally but higher aldosterone with angiotensin II stimulation. In conclusion, we documented that not only was there a sex-mediated difference in the activity of aldosterone’s biosynthesis, but also these differences at the molecular level, help explain the variable reports on aldosterone’s circulating levels. Basally, both in-vivo and ex-vivo, males had higher aldosterone levels, likely secondary to higher aldosterone secretagogue levels. However, in response to acute stimulation, aldosterone levels are higher in females because of the greater levels and/or activity of their StAR/CYP11A1.
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