It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis.

Polycystic ovary syndrome (PCOS) is now recognized as an important metabolic as well as reproductive disorder conferring substantially increased risk for type 2 diabetes. Affected women have marked insulin resistance, independent of obesity. This article summarizes the state of the science since we last reviewed the field in the Endocrine Reviews in 1997. There is general agreement that obese women with PCOS are insulin resistant, but some groups of lean affected women may have normal insulin sensitivity. There is a post-binding defect in receptor signaling likely due to increased receptor and insulin receptor substrate-1 serine phosphorylation that selectively affects metabolic but not mitogenic pathways in classic insulin target tissues and in the ovary. Constitutive activation of serine kinases in the MAPK-ERK pathway may contribute to resistance to insulin's metabolic actions in skeletal muscle. Insulin functions as a co-gonadotropin through its cognate receptor to modulate ovarian steroidogenesis. Ge...

Insulin Resistance and the Polycystic Ovary Syndrome Revisited: An Update on Mechanisms and Implications

Polycystic ovary syndrome (PCOS) is characterized by a constellation of clinical symptoms that include irregular menses due to chronic oligo-ovulation, phenotypic features of hyperandrogenism, and obesity The term “polycystic ovary” refers to ovarian morphology with increased ovarian stroma and a ring of cortical follicles Core biochemical features include hyperandrogenism and insulin resistance The pathogenesis of PCOS remains a topic of debate Treatment of PCOS typically focuses on mitigating the impact of hyperandrogenism, insulin resistance, and chronic oligo-ovulation and restoring fertility when desired

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Polycystic ovary syndrome.

Metformin is an insulin-sensitizing agent with potent antihyperglycemic properties. Its efficacy in reducing hyperglycemia in type 2 diabetes mellitus is similar to that of sulfonylureas, thiazolidinediones, and insulin. Metformin-based combination therapy is often superior to therapy with a single hypoglycemic agent. The antihyperglycemic properties of metformin are mainly attributed to suppressed hepatic glucose production, especially hepatic gluconeogenesis, and increased peripheral tissue insulin sensitivity. Although the precise mechanism of hypoglycemic action of metformin remains unclear, it probably interrupts mitochondrial oxidative processes in the liver and corrects abnormalities of intracellular calcium metabolism in insulin-sensitive tissues (liver, skeletal muscle, and adipocytes) and cardiovascular tissue.

http://morelife.org/references/full_papers/12093242.pdf

Metformin: an update.

The body is equipped with broad-specificity transporters for the excretion and distribution of endogeneous organic cations and for the uptake, elimination and distribution of cationic drugs, toxins and environmental waste products. This group of transporters consists of the electrogenic cation transporters OCT1-3 (SLC22A1-3), the cation and carnitine transporters OCTN1 (SLC22A4), OCTN2 (SLC22A5) and OCT6 (SLC22A16), and the proton/cation antiporters MATE1, MATE2-K and MATE2-B. The transporters show broadly overlapping sites of expression in many tissues such as small intestine, liver, kidney, heart, skeletal muscle, placenta, lung, brain, cells of the immune system, and tumors. In epithelial cells they may be located in the basolateral or luminal membranes. Transcellular cation movement in small intestine, kidney and liver is mediated by the combined action of electrogenic OCT-type uptake systems and MATE-type efflux transporters that operate as cation/proton antiporters. Recent data showed that OCT-type transporters participate in the regulation of extracellular concentrations of neurotransmitters in brain, mediate the release of acetylcholine in non-neuronal cholinergic reactions, and are critically involved in the regulation of histamine release from basophils. The recent identification of polymorphisms in human OCTs and OCTNs allows the identification of patients with an increased risk for adverse drug reactions. Transport studies with expressed OCTs will help to optimize pharmacokinetics during development of new drugs.

Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications.

Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)

Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy☆

Sex steroids, lipids, and lipoprotein cholesterols in women with subclinical and overt hypothyroidism before and after L-thyroxine therapy.

The aim of the current study of 18 hyperandrogenic women was to determine the affects of ketoconazole (KTZ), an oral synthetic antifungal imidazole derivative that inhibits gonadal and adrenal steroidogenesis, on lipids, lipoprotein cholesterols, apolipoproteins, endogenous sex steroid hormones, and their interactions. Eighteen hyperandrogenic women, ages 18 to 35, with a history of severe acne and/or hirsutism, were randomly divided into two groups of nine, both receiving KTZ (group 1,400 mg/d; group 2,800 mg/d) for 10 days. In groups 1 and 2, KTZ therapy reduced cholesterol (10%, P ≤ .01; 19%, P ≤ .05) and low-density lipoprotein (LDL)-cholesterol (13%, P ≤ .05; 33%, P ≤ .025), and increased apoplipoprotein (apo) A1 (7%, P ≤ .005; 13%, P ≤ .01). KTZ, 800 mg/d, decreased apo B (21%, P ≤ .005), and lowered the ratio of LDL-cholesterol to high-density lipoprotein (HDL)-cholesterol (40%, P ≤ .01). KTZ therapy more than doubled the levels of estradiol (E2) in both groups (136%, P ≤ .01; 171%, P ≤ .01) and, in the high-dose group, decreased the levels of free testosterone (FT) (48%, P ≤ .05) and dehydroepiandrosterone-sulfate (DHEA-S) (36%, P ≤ .005). The reductions of total and LDL-cholesterol appear to be attributable to the increases in E2 and possibly to the decrease in FT. KTZ therapy may have beneficial effects on atherogenic lipid and lipoprotein patterns in women with hyperandrogenicity.

Effect of ketoconazole on plasma sex hormones, lipids, lipoproteins, and apolipoproteins in hyperandrogenic women

Objectives: To compare the effect of two routes of hormonal therapy (HT) on blood pressure, insulin resistance indexes, Tg/ HDL-C ratio in postmenopausal hypertensive women Methods: A clinical study was performed in 19 postmenopausal women All women were treated with equine conjugated estrogens (Premarin®: 0,625mg) for 8 weeks (O-HT) After 4 weeks period without treatment, patients were switched to transdermal estrogen therapy (TD-HT) using 17β estradiol (Estraderm®, 50mg) Medroxyprogesterone (5mg, Provera®) acetate was administered during 3rd-4 th week and seventh-eighth week in each treatment cycle Blood pressure and blood samples were taken at baseline and after each period o treatment Laboratory protocol included determinations of FSH, estradiol, androstendione, DHEAS and glucose and insulin during a standard oral glucose test Results: HT caused a significant decrease in BP but TD-HT was more efficient (p<0,05) Oral treatment was associated with a significant decrease in Tg/C-HDL, Ct/C-HDL indexes and a significant increase in HDL-C Plasma Tg decreased significantly after both routes of treatment with more pronounced effect during TD-HT No significant differences between groups were observed in plasma glucose and insulin during fasting and post oral glucose load TD-HT showed a significant decrease in HOMA-IR and a significant increase in sensitivity indexes QUICKI and ISI Serum androstenedione levels were decreased after both routes of treatment (p<0,05) Conclusions: Combined cyclical HT has beneficial effects on blood pressure, lipoproteins, Tg/C-HDL ratio and insulin action indexes leading to a lower risk of cardiovascular disease in postmenopausal hypertensive women We suggest that in this population, transdermal HT should be considered as a first therapeutic option

Efectos de dos esquemas de TH combinada cíclica sobre la presión arterial, lipoproteínas, índices de resistencia a la insulina y cociente TG/C-HDL en mujeres posmenopáusicas hipertensas

Metformine therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoproteine (a), and immunoreactive insuline levels in patients with the pcos.

Soaira Mendoza

Papers

Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating normal menses and pregnancy☆

Sex steroids, lipids, and lipoprotein cholesterols in women with subclinical and overt hypothyroidism before and after L-thyroxine therapy.

Effect of ketoconazole on plasma sex hormones, lipids, lipoproteins, and apolipoproteins in hyperandrogenic women

Efectos de dos esquemas de TH combinada cíclica sobre la presión arterial, lipoproteínas, índices de resistencia a la insulina y cociente TG/C-HDL en mujeres posmenopáusicas hipertensas

Metformine therapy is associated with a decrease in plasma plasminogen activator inhibitor-1, lipoproteine (a), and immunoreactive insuline levels in patients with the pcos.