An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

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Homocysteine and Cardiovascular Disease

Objective: The Androgen Excess Society (AES) charged a task force to review all available data and recommend an evidence-based definition for polycystic ovary syndrome (PCOS), whether already in use or not, to guide clinical diagnosis and future research. Participants: Participants included expert investigators in the field. Evidence: Based on a systematic review of the published peer-reviewed medical literature, by querying MEDLINE databases, we tried to identify studies evaluating the epidemiology or phenotypic aspects of PCOS. Consensus Process: The task force drafted the initial report, following a consensus process via electronic communication, which was then reviewed and critiqued by the AES Board of Directors. No section was finalized until all members were satisfied with the contents and minority opinions noted. Statements that were not supported by peer-reviewed evidence were not included. Conclusions: Based on the available data, it is the view of the AES Task Force on the Phenotype of PCOS that...

https://www.ae-society.org/pdf/guidelines/Criteria.pdf

Position statement: Criteria for defining polycystic ovary syndrome as a predominantly hyperandrogenic syndrome: An androgen excess society guideline

Background Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. Methods We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. Results After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 μmol per liter had died, as compared ...

https://www.nejm.org/doi/pdf/10.1056/NEJM199707243370403

Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

The polycystic ovary syndrome is one of the most common hormonal disorders affecting women It has multiple components — reproductive, metabolic, and cardiovascular — with health implications for the patient's entire life span This review addresses current concepts regarding the diagnosis, cause, and treatment of the condition

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Polycystic ovary syndrome.

https://www.fertstert.org/article/S0015-0282(08)01392-7/pdf

The Androgen Excess and PCOS Society criteria for the polycystic ovary syndrome: the complete task force report

Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion : a pilot study

In 138 oligo-amenorrheic white women with polycystic ovary syndrome (PCOS) (31+/-9-years-old), our first specific aim was to assess the incidence of the metabolic syndrome and to compare metabolic syndrome abnormalities in women with PCOS to those in the National Health and Nutrition Examination Survey (NHANES) III cohort of 1,887 white women. Our second aim was to determine whether metformin (2.55 g/d) and a diet of 1,500 calories, 26% protein, 44% carbohydrate (42% of carbohydrate complex), 30% fat (polyunsaturate/saturate ratio [P/S]=2/1), would ameliorate metabolic syndrome abnormalities in women with both PCOS and metabolic syndrome. The metabolic syndrome was present in 64 (46%) of the women with PCOS. In these 64 women, there were abnormalities in waist circumference (98%), high-density lipoprotein cholesterol (HDL-C) (95%), blood pressure (70%), triglycerides (56%), and glucose (11%). In these 64 women, mean +/- SD waist circumference was 116+/-15 cm, triglyceride 192+/-152 mg/dL, HDL-C 39+/-7 mg/dL, systolic blood pressure 131+/-13 mm Hg, diastolic blood pressure 83+/-7 mm Hg, and serum glucose 94+/-22 mg/dL. Serum insulin was high (>17 microU/mL) in 42 of the 64 women (66%). After age adjustment, 46.4%+/-4.2% of women with PCOS had the metabolic syndrome (> or =3 abnormalities) versus 22.8%+/-1.1% of NHANES III women, P or =150 mg/dL), 47 had low HDL-C ( or =130 mm Hg), 16 had high diastolic blood pressure (> or =85 mm Hg), and 5 had glucose > or = 110 mg/dL. On metformin plus diet at 6 months, triglycerides moved within guidelines in 10 of 29 (34%) women, HDL-C in 6 of 47 (13%), systolic blood pressure in 16 of 26 (62%), diastolic blood pressure in 10 of 16 (63%), and glucose in 3 of 5 (60%). Metformin and diet ameliorate many of the features of the metabolic syndrome, present in 46% of women with PCOS in the current study, and should reduce risk for atherothrombosis and type 2 diabetes mellitus (DM) in PCOS.

Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome.

BACKGROUND: We sought to determine whether metformin, which had facilitated conception in 72 oligoamenorrhoeic women with polycystic ovary syndrome (PCOS), would safely reduce the rate of first trimester spontaneous abortion (SAB) and increase the number of live births without teratogenicity. METHODS: Seventytwo oligoamenorrheic women with PCOS conceived on metformin (2.55 g/day). They were prospectively assessed in an outpatient clinical research centre. Outcome measures included number of first trimester SAB, live births, normal ongoing pregnancies ≥13 weeks, gestational diabetes (GD), congenital defects (CD), birthweight and height, as well as weight, height, and motor and social development during the first 6 months of life. RESULTS: Of the 84 fetuses, to date there have been 63 normal live births without CD (75%), 14 first trimester SAB (17%), and seven ongoing pregnancies ≥13 weeks with normal sonograms without CD (8%). Previously, without metformin, 40 of the 72 women had 100 pregnancies (100 fetuses) with 34 (34%) live births and 62 (62%) first trimester SAB. In current pregnancies on metformin in these 40 women (46 pregnancies, 47 fetuses), there have been 33 live births (70%), two pregnancies ongoing ≥13 weeks (4%), and 12 SAB (26%) (P < 0.0001). There was no maternal lactic acidosis, and no maternal or neonatal hypoglycaemia. Fasting entry serum insulin was a significant explanatory variable for total (previous and current) first trimester SAB, odds ratio 1.32 (for each 5 µU/ml rise in insulin), 95% CI 1.09– 1.60 (P 0.005). On metformin, GD developed in 4% of pregnancies versus 26% of previous pregnancies without metformin, P 0.025. There have been no major CD in the 63 live births or CD by sonography in the seven fetuses ≤13 weeks. In the 63 live births, neither weight nor height differed from the normal neonatal population. At 6 month follow-up, height was greater (P 0.008) and weight did not differ from the normal paediatric population; motor and social development were normal. CONCLUSIONS: Metformin therapy during pregnancy in women with PCOS was safely associated with reduction in SAB and in GD, was not teratogenic, and did not adversely affect birthweight or height, or height, weight, and motor and social development at 3 and 6 months of life.

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Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin

https://www.fertstert.org/article/S0015-0282(01)03202-2/pdf

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome

In 43 amenorrheic women with polycystic ovary syndrome (PCOS), 31 (74%) with fasting hyperinsulinemia (> or =20 microU/mL), our aim was to determine whether Metformin (Bristol-Myers Squibb, Princeton, NJ), which reduces hyperinsulinemia, would reverse the endocrinopathy of PCOS, allowing resumption of regular normal menses. A second aim was to assess the effects of weight loss versus other Metformin-induced effects on ovarian function, and to determine if there were different responses to Metformin between those who lost weight and those who did not. A third aim was to assess associations between PCOS, 4G/5G polymorphism in the promoter sequence of the plasminogen activator inhibitor-1 gene (PAI-1 gene), and PAI activity (PAI-Fx). Of the 43 women, 40 (93%) had normal fasting blood glucose and 37 had normal hemoglobin A1C (HgA1C); onlythree (7%) had type 2 diabetes mellitus. Metformin (1.5 to 2.25 g/d) was given for 6.1+/-5.1 months (range, 1.5 to 24), to 16 patients for less than 3 months, to 12 for 3 to 6 months, and to 15 for at least 6 months. On Metformin, 39 of 43 patients (91%) resumed normal menses. The percentage of women resuming normal menses did not differ among treatment duration groups (P .1). The body mass index (BMI) decreased from 36.4 + 7 Kg/m2 at study entry to 35.1+/-6.7 on Metformin (P=.0008). Of 43 patients, 28 (67%) lost weight (1 to 69 pounds), with nine (21%) losing at least 12 pounds. On Metformin, the median fasting serum insulin decreased from 26 microU/mL to 22 (P=.019), testosterone decreased from 61 ng/dL to 47 (P=.003), and estradiol increased from 41 pg/mL to 71 (P=.0001). Metformin-induced improvements in ovarian function were independent of weight loss (testosterone decrease, P .05) between those who lost weight and those who did not, excepting Lp(a), which increased 4 mg/dL in those who lost weight and decreased 9 mg/dL in those who did not (P = .003). The change in response variables on Metformin did not differ among the five quintiles of weight loss, excepting fasting glucose (P or =22 U/mL, 28% v3%, chi(2)=10.1, P=.001). Metformin reduces the endocrinopathy of PCOS, allowing resumption of normal menses in most (91%) previously amenorrheic women with PCOS.

Luann Sieve-Smith

Papers

Continuing metformin throughout pregnancy in women with polycystic ovary syndrome appears to safely reduce first-trimester spontaneous abortion : a pilot study

Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome.

Pregnancy outcomes among women with polycystic ovary syndrome treated with metformin

Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome

Metformin-induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women with the polycystic ovary syndrome.