Metformin is not associated with pre-eclampsia in pregnancy in women with PCOS, and appears to be safe for mother and fetus.

No abstract

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylene tetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 21 smoking BD patients (14 men [2 siblings], 7 women; 20 white, 1 African-American), compared to 21 age-gender-race matched healthy controls, 5A/6A stromelysin- 1 homozygosity was present in 7 of 21 (33%) BD cases versus 5 of 21 (24%) controls (risk ratio 1.4; 95% confidence interval [CI] 0.5-3.7), and eNOS T-786C homozygosity was present in 3 of 21 (14%) BD cases versus 1 of 21 (5%) controls (risk ratio 3.0; 95% CI 0.3-26.6). C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity was present in 7 of 21 cases (33%) versus 11 of 21 controls (52%) (risk ratio 0.6; 95% CI 0.3-1.3). In 18 patients who stopped and 3 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, superficial phlebitis, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In 15 patients, to increase vasodilatory NO via endothelial NO synthase, l-arginine (15 g/day) was given, along with folic acid (5 mg), vitamin B6 (100 mg), and B12 (2000 mg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months receiving l-arginine-folic acid, 11 of 15 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo/heterozygous for stromelysin-1 5A/6A and eNOS T-786C mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by l-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.

BackgroundSex hormone binding globulin (SHBG), a glycoprotein produced by hepatocytes that transports testosterone and other steroids in plasma, is a marker for developing metabolic syndrome and T2DM. SHBG is present in umbilical cord blood where it may be epigenetically regulated. This study was conducted to investigate whether the fetal environment, based on maternal pre-pregnancy weight, pregnancy weight gain or smoking during pregnancy, influence SHBG in newborns.MethodsMaternal and newborn characteristics and SHBG levels and other variables were measured in cord and day 2 heel-stick blood samples in 60 healthy full-term singleton babies (31 F, 29 M).ResultsSHBG levels varied nearly fivefold among male and female newborns and were unrelated to sex, neonatal adiposity, determined by the Ponderal index and skinfold thickness, nor TNF∝ in cord blood. There were also no statistically significant associations between pre-pregnancy weight or pregnancy weight gain and newborn SHBG levels. However, cord blood SHBG was higher and insulin levels were lower when mothers were smokers, but normalized by day 2.DiscussionWhile SHBG levels are low in obese children and adults, and portend the development of metabolic syndrome and T2DM, our study of healthy babies born to normal women, found no connection between maternal obesity or newborn adiposity and SHBG levels in newborns. Insofar as women who smoked during pregnancy were thinner and had lower cord blood insulin levels than nonsmokers, higher SHBG in their newborns at birth might have been due to insulin sensitivity, or perhaps to an effect of smoking on placental gene expression.ConclusionsFactors other than maternal weight and pregnancy weight gain appear to be the major determinants of SHBG in newborns. Higher SHBG levels when mothers smoke during pregnancy may contribute to overweight beginning later in childhood. Whether newborn SHBG levels predict the development of overweight and metabolic syndrome remains to be determined.

Buerger's disease (BD) etiologies are poorly understood. Beyond smoking cessation, medical-surgical treatments have limited success. We hypothesized that mutations associated with arterial vasospasm (stromelysin-1 5A/6A, eNOS T-786C) and C677T-A1298C methylenetetrahydrofolate reductase (MTHFR) interacted with cigarette-cannabis smoking, reducing vasodilatory nitric oxide (NO), promoting arterial spasm-thrombosis. Of 19 smoking BD patients (13 men [2 siblings], ± women, 18 Caucasian, 1 African American), compared to 200 healthy Caucasian controls, BD patients were more likely to have 6A6A stromelysin-1 homozygosity (7/19 [37%] vs 46/200 [23%]) and to have eNOS T-786C homozygosity (3/19 [16%] vs 22/200 [11%]), but these patient-control differences were not significant, p = .4, 0.5. C677T MTHFR homozygosity or compound C677T-A1298C heterozygosity did not differ in patients vs controls (6/19 [32%] vs 70/200 [35%]), p = .8. In 9 patients who stopped and 1 who continued smoking, all stromelysin-1 5A/6A and/or eNOS heterozygotes-homozygotes, lower limb gangrenous ulcers, and intractable ischemic rest pain with arterial occlusion progressed despite conventional medical therapy, threatening amputation. In these 10 patients, to increase vasodilatory NO via endothelial NO synthase, L-arginine (15 g/day) was given, along with folic acid 5 mg, vitamin B6 (100 mg), and B12 (2,000 μg/day) to optimize homocysteine metabolism and reduce asymmetric dimethylarginine, a NO synthase inhibitor. Unexpectedly quickly and strikingly, within 8 weeks to 8 months on L-arginine-folic acid, all 10 treated patients improved with uniform pain reduction, ulcer healing, and in 5, full recovery of previously absent peripheral pulses. In smokers homo-heterozygous for stromelysin-1 5A/6A, eNOS T-786C, and C677T-A1298C MTHFR mutations, we speculate that the development and severity of BD are related to a gene-environment vasospastic interaction with reduced NO-mediated vasodilatation. Increasing NO production by L-arginine while optimizing homocysteine metabolism by folic acid-B6-B12 may have therapeutic benefit. Further blinded, placebo-controlled studies are needed to determine whether our observations can be generalized to larger BD cohorts.