Sandbox 2

Historical Perspective

• The term "metabolic syndrome" dates back to at least the late 1950s, but came into common usage in the late 1970s to describe various associations of risk factors with diabetes.
• In 1947, Dr. Jean Vague proposed a theory that upper body obesity predisposed to diabetes, atherosclerosis, gout, and calculi.
• In 1967, Avogaro, Crepaldi and co-workers discovered obese patients with diabetes, hypercholesterolemia, and marked hypertriglyceridemia improved when they were put on a hypocaloric, low carbohydrate diet.
• In 1977, Haller coined the term "metabolic syndrome" for the first time when describing the additive effects of risk factors on atherosclerosis.
• In 1977, Singer coined the term hyperlipoproteinemia to describe the associations of obesity, gout, diabetes mellitus, and hypertension with metabolic syndrome.
• In 1977 and 1978, Gerald B. Phillips developed the concept that risk factors for myocardial infarction are not only associated with heart disease, but also with aging, obesity and other clinical states.
• In 1988, Gerald M. Reaven proposed insulin resistance as the underlying factor and named the constellation of abnormalities as Syndrome X.

Pathophysiology

• Hyperinsulinemia is noted in 50% to 70% of PCOS patients. It is defined as impaired action of insulin on glucose transport and antilipolysis in adipocytes in the presence of normal insulin binding.
• Hyperinsulinemia causes or exacerbates hyperandrogenemia. Increased insulin levels at the ovarian level lead to increased androgen production from the ovarian thecal cells.
• Also, by suppressing hepatic production of sex hormone binding globulin (SHBG), insulin increases unbound levels of testosterone.
• At the level of the granulosa cell, insulin amplifies the response of granulosa cells to LH. Thus, these cells undergo abnormal differentiation and premature arrest of follicular growth, and thus anovulation.
• Elevated androgen levels also lead to decreased levels of SHBG. Greater unbound androgen levels are likely to produce a greater clinical response, such as hirsutism and acne.
• Most patients with PCOS show evidence of clinical hyperandrogenism.
• In such cases, measurement of free testosterone should be considered, although most direct assays for free testosterone have limited value for evaluating the hyperandrogenic woman. The methods recommended at the consensus meeting to determine free testosterone are by equilibrium dialysis, by calculation of free testosterone from measurement of SHBG and total testosterone, or by ammonium sulfate precipitation. DHEAS may be measured, because a small percentage of patients with PCOS have isolated elevations in this hormone.
• Another key feature of PCOS is altered gonadotropin dynamics. Several studies have shown higher LH pulse and amplitude in women with PCOS.
• Although a higher LH level drives the ovarian theca cells to produce more androgens, insufficient follicle-stimulating hormone (FSH) may be the more immediate cause of anovulation.
• In most women with PCOS, LH levels are elevated or the LH/FSH ratio is high; however, the mean LH pulse amplitude is attenuated in obese women with PCOS. Thus, the LH value or LH/FSH ratio is not helpful in establishing this diagnosis in such patients.

Screening

According to the Endocrine Society clinical guidelines, screening for metabolic syndrome is recommended every 3 years among patients with one or more risk factors. Screening assessment includes measurement of blood pressure, waist circumference, fasting lipid profile, and fasting glucose.