The prevalence of benign breast disease in women with polycystic ovary syndrome: a review of a 12-year follow-up.

A cross-sectional study of benign breast disease (BBD) was conducted to determine the actual prevalence and follow-up importance of BBD among women with polycystic ovary syndrome (PCOS) in conjunction with an ongoing prospective cohort study. The present study involved a subset of the original group of 244 women with a diagnosis of PCOS and 244 control women matched by age and race. A total of 240 women (116 cases and 124 controls) were included in the present analysis. The majority of women in each group were Caucasians (93 and 96%, respectively). The median age was 46 years in the cases and 47 years in the controls. Screening mammography begins at the age of 40 and has been carried out in 69% of cases and 66% of controls since the study began. Family history of breast disease was observed in 27 cases of both the groups (p > 0.05). Neither fibrocystic breast disease, lump thickening, calcification, fibroadenoma, pain, redness, discharge nor hyperplasia showed a significantly higher prevalence rate in cases than in controls. Eleven (9%) women with PCOS and 21 (17%) controls underwent diagnostic or curative surgery (relative risk: 0.56). These results, in contrast to the previously published literature, do not allow us to conclude that there is a higher risk for BBD among women with PCOS, and the proportion of women with a positive family history of breast cancer was significantly greater in women with PCOS compared with controls. Our observation is that having PCOS does not appear to affect surgeons' decisions to remove BBD.

The relationship between C-reactive protein and carotid intima-media wall thickness in middle-aged women with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is associated with premature carotid atherosclerosis. C-Reactive protein (CRP) has been implicated as a vascular disease risk factor. The objective of this study was to determine whether elevated CRP is associated with increased carotid intima-media wall thickness (IMT) in PCOS women. Forty-seven PCOS patients and 59 similarly aged controls were screened for cardiovascular risk factors and concurrently underwent carotid ultrasonography (1996-1999). The main outcome measure was carotid IMT. CRP was significantly higher in PCOS patients than in controls (3.4 vs. 2.1 mg/dl; P = 0.002). In regression modeling, PCOS associated with IMT independently of CRP and age (P = 0.019). Body mass index reduced the association of PCOS and CRP with IMT and was also associated with IMT (P = 0.029). The CRP-IMT relationship was attenuated when either insulin or visceral fat was included in the PCOS-age-CRP model (P = 0.197 and P = 0.550, respectively). PCOS remained associated with IMT independent of insulin (P = 0.033) or visceral fat (P = 0.040). CRP does not appreciably mediate the effect of PCOS on IMT. Obesity partially explained the influence of PCOS and CRP on IMT. The effect of body mass index on the PCOS-IMT relationship was not completely determined by hyperinsulinemia or visceral fat, and might be mediated by other aspects of PCOS-related adiposity.

Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome.

Women with polycystic ovary syndrome (PCOS) exhibit an adverse cardiovascular risk profile, characteristic of the metabolic cardiovascular syndrome (MCS). The aim of this study was to determine the prevalence of coronary artery (CAC) and aortic (AC) calcification among middle-aged PCOS cases and controls and to explore the relationship among calcification, MCS, and other cardiovascular risk factors assessed 9 yr earlier. This was a prospective study of 61 PCOS cases and 85 similarly aged controls screened in 1993-1994 for risk factors and reevaluated in 2001-2002. The main outcome measures were CAC and AC, measured by electron beam tomography. Women with PCOS had a higher prevalence of CAC (45.9% vs. 30.6%) and AC (68.9% vs. 55.3%) than controls. After adjustment for age and body mass index, PCOS was a significant predictor of CAC (odds ratio = 2.31; P = 0.049). PCOS subjects were also 4.4 times more likely to meet the criteria for MCS than controls. High-density lipoprotein cholesterol and insulin appeared to mediate the PCOS influence on CAC. Interestingly, total testosterone was an independent risk factor for AC in all subjects after controlling for PCOS, age, and body mass index (P = 0.034). We conclude that women with PCOS are at increased risk of MCS and demonstrate increased CAC and AC compared with controls. Components of MCS mediate the association between PCOS and CAC, independently of obesity.

Dietary intake, physical activity, and obesity in women with polycystic ovary syndrome.

OBJECTIVE: To determine whether dietary intake and physical activity contribute to obesity in women with polycystic ovary syndrome (PCOS). DESIGN: Case-control study. SUBJECTS: A total of 84 cases and 79 neighborhood controls of similar age. MEASUREMENTS: Fasting insulin, body mass index (BMI, kg/m2), waist/hip ratio, Block Food Frequency Questionnaire, Paffenbarger Physical Activity Questionnaire. RESULTS: Although women with PCOS had a higher BMI than control women, an overall comparison of women with and without PCOS showed no significant difference in dietary intake. However, stratification by BMI revealed that lean women with PCOS reported significantly lower energy intake than lean women without PCOS. CONCLUSION: Differences in dietary intake and physical activity alone are not sufficient to explain differences in weight between women with and without PCOS. Further research is necessary to determine the relative contributions of lifestyle factors and metabolism to obesity in PCOS.

Assessment of the disturbances in metabolic homeostasis: a hypothesis of synergism.

Based on the hypothesis that a synergistic interaction between triiodothyronine (T(3)) and insulin contributes to abnormalities in glucose and other metabolic pathways, the mechanisms underlying the impairment of metabolic homeostasis (MH) and the development of type-2 diabetes (DM) were investigated via a proposed homeostatic model, [(FG*TG)/T3*FI)]. The MH model characterizes the relationship between T(3) and insulin and the levels of triglycerides (TG), fasting insulin (FI), and fasting glucose (FG) and is introduced as a clinical method to assess insulin sensitivity and the status of metabolic homeostasis in lieu of current screening models advocated by the by American Diabetic Association (ADA). The present study validated the hypothetical model in a sample of 110 African-American women.

Cardiovascular risk in women with polycystic ovary syndrome.

Compared with normal cycling women of similar age, women with polycystic ovary syndrome (PCOS) have an adverse lipid profile and an increased prevalence of Type II diabetes and hypertension. These woman also appear to have greater subclinical atherosclerotic disease, as demonstrated by greater carotid intimamedia wall thickness and higher levels of coronary calcification. Given the high prevalence of PCOS in the female population, this condition may potentially account for a significant proportion of the atherosclerotic heart disease observed in younger women. This article reviews the issues and uncertainties surrounding the PCOS-CHD association.

Polycystic ovary syndrome, androgen excess, and the impact on bone.

Polycystic ovary syndrome (PCOS) is a unique, natural model for the study of the influence of androgen excess on bone mass among women. Both thin and obese women develop PCOS, a presentation that allows for the evaluation of the effects of life-long obesity, alterations in body composition (central adiposity), and related metabolic abnormalities (hyperandrogenemia, hyperinsulinemia) on the skeleton. The relatively high prevalence of PCOS and its manifestation early in life render this disorder of particular importance in assessing the influence of androgens and androgen-estrogen balance on the attainment of maximal bone mass and subsequent development of osteoporosis later in life.

Evidence for association between polycystic ovary syndrome and premature carotid atherosclerosis in middle-aged women.

Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by obesity, hyperandrogenism, and insulin resistance. An adverse lipid profile has also been observed in PCOS-affected women, suggesting that these individuals may be at increased risk for coronary heart disease at a young age. The objective of the present study was to evaluate subclinical atherosclerosis among women with PCOS and age-matched control subjects. A total of 125 white PCOS cases and 142 controls, aged >/=30 years were recruited. Collection of baseline sociodemographic data, reproductive hormone levels, and cardiovascular risk factors was conducted from 1992 to 1994. During follow-up (1996 to 1999), these women underwent B-mode ultrasonography of the carotid arteries for the evaluation of carotid intima-media wall thickness (IMT) and the prevalence of plaque. A significant difference was observed in the distribution of carotid plaque among PCOS cases compared with controls: 7.2% (9 of 125) of PCOS cases had a plaque index of >/=3 compared with 0.7% (1 of 142) of similarly aged controls (P=0.05). Overall and in the group aged 30 to 44 years, no difference was noted in mean carotid IMT between PCOS cases and controls. Among women aged >/=45 years, PCOS cases had significantly greater mean IMT than did control women (0.78+/-0.03 versus 0.70+/-0.01 mm, P:=0. 005). This difference remained significant after adjustment for age and BMI (P:<0.05). These results suggest that (1) lifelong exposure to an adverse cardiovascular risk profile in women with PCOS may lead to premature atherosclerosis, and (2) the PCOS-IMT association is explained in part by weight and fat distribution and associated risk factors. There may be an independent effect of PCOS unexplained by the above variables that is related to the hormonal dysregulation of this condition.

Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome.

OBJECTIVE: To determine whether testosterone levels change as women with the polycystic ovary syndrome (PCOS) grow older. DESIGN: A follow-up cross-sectional study of a cohort of women with PCOS identified up to 20-25 years ago. SETTING: Women with PCOS were recruited primarily from practice records between 1970 and 1990. Voter registration tapes and household directories were used to identify age-, race-, and neighborhood-matched controls. PARTICIPANT(S): Eighty-four women with PCOS, 20-57 years of age, and 37 age-matched controls participating in a study of the risk for cardiovascular disease in women with PCOS. INTERVENTION(S): Clinical data were collected by questionnaire and fasting blood samples were obtained randomly throughout the menstrual cycle. MAIN OUTCOME MEASURE(S): Total and non-SHBG-bound testosterone levels. RESULT(S): Total and non-SHBG-bound testosterone levels were similar in women with PCOS who were 20-42 years of age but were reduced by approximately 50% among women 42-47 years of age and remained stable in women older than 47 years of age. Testosterone levels were increased in younger and older women with PCOS compared with controls but were similar to controls in women 42-47 years of age. CONCLUSION(S): Hyperandrogenism partly resolves before menopause in women with PCOS. This change may explain the tendency of women with PCOS to cycle regularly as they grow older. Testosterone levels remain elevated in older women with PCOS, however, and may contribute to their increased risk for cardiovascular disease, endometrial cancer, and other diseases.

A fusogenic protein from rat brain microsomal membranes: partial purification and reconstitution into liposomes.

The procedures for purification and reconstitution of rat brain microsomal membrane protein that causes fusion of liposomes at acidic pH are described. A 1,860-fold purification was achieved, starting from the detergent-solubilized microsomal membranes. The fusion process was assayed spectrofluorimetrically by monitoring the formation of terbium-dipicolinic acid complex (Wilschut, J. et al. 1980. Biochemistry 19:6011-6021) evoked by the protein after mixing of two populations of liposomes. The fusogenic activity of the protein inserted into the membrane of Tb3+-containing vesicles was found to be strongly dependent on phospholipid composition and was higher in vesicles enriched with exogenous phosphatidylserine, phosphatidylglycerol and phosphatidylethanolamine than in those prepared with an excess of phosphatidylcholine. The vesicles enriched in negatively charged phospholipids were bound to Concanavalin A coupled to Sepharose-4B and could be released from this column only in the presence of a high concentration of alpha-methylmannopyranoside and detergent, indicating a glycoprotein nature of the fusogenic protein. Furthermore, these data show that protein inserted into membrane has its oligosaccharide chains exposed to the environment.

Intramitochondrial distribution and transport of phosphatidylserine and its decarboxylation product, phosphatidylethanolamine. Application of pyrene-labeled species.

To investigate the mechanism of intramitochondrial translocation of phosphatidylserine and its decarboxylation product, phosphatidylethanolamine, the distribution of these lipids between the outer (OM) and inner (IM) mitochondrial membranes, as well as their transversal and lateral distribution in OM were studied. Fluorescent, pyrenyl derivatives of phosphatidylserine (PyrxPS) and phosphatidylethanolamine (PyrxPE) species were employed because they allow: (i), direct monitoring of PS (and PE) loading to the mitochondria; (ii) assay of PS decarboxylation by high-performance liquid chromatography with fluorescence detection and (iii), determination of the lateral distributions of PS and PE within the mitochondrial membranes. All PyrxPS species tested were efficiently decarboxylated by the solubilized decarboxylase and thus the distribution of the endogenous PE could be also studied. When the PyrxPS species were loaded to isolated mitochondria very little, if any, of the loaded PyrxPS or of the PyrxPE product was found in IM independent of the time and temperature of incubation, strongly suggesting that these lipids either never enter IM or their residence there is only transient. When mitochondria preloaded with Pyr4PS were incubated with an excess of acceptor vesicles in the presence of the lipid transfer protein, 80% of Pyr4PS and 30-40% of the Pyr4PE product were transported to the acceptor vesicles, indicating that at least corresponding fractions of these lipid were located in, or were in rapid equilibrium with the outer leaflet of OM. Since the decarboxylase is located in the inner membrane, these results signify that both PS and PE must be able to move readily across OM. Determination of the excimer to monomer ratio as the function of pyrenyl lipid concentration in mitochondria (i.e., OM) gave parallel results for PyrxPS and -PE species suggesting the lateral distribution of PS and PE in OM is similar and thus there is no specific enrichment of PS to the contact sites. To investigate the mechanism of PS transport from the outer leaflet to the decarboxylation site, the influence of PyrxPS hydrophobicity, i.e., pyrenylacyl chain length, on the rate of decarboxylation was determined. The variation of the length of the pyrenyl acyl chain from 4 to 12 carbons did not significantly affect the rate of PyrxPS decarboxylation in intact mitochondria, indicating that the transport of PS from the outer leaflet of OM to the site of decarboxylation takes place by lateral diffusion rather than by spontaneous or protein-mediated transport. The implications of these findings on the mechanism of intramitochondrial transport of PS and PE are discussed in terms of alternative models.

Interaction of caldesmon with phospholipids.

The interaction of caldesmon with liposomes composed of various phospholipids has been examined by tryptophan fluorescence spectroscopy. The results indicate that caldesmon makes its strongest complex with phosphatidylserine (PS) vesicles (Kass. = 1.45 x 10(5) M-1). Both electrostatic and hydrophobic interactions contribute to the stability of this complex. The site for strong binding of PS seems to be located in the N-terminal part of the 34 kDa C-terminal fragment of caldesmon. Binding of PS at this site results in displacement of calmodulin from its complex with caldesmon.

Serine base-exchange in rat liver microsomes: effect of phospholipids.

We enriched liver microsomes in lipid classes and molecular species disrupting membranes with octyl glucoside and reassembling them by detergent removal. Phosphatidylethanolamine incorporated into membranes better than phosphatidylserine or phosphatidylcholine. In addition, the degree of incorporation depended on the unsaturation of fatty acyl-chains. The enrichment of the membranes with phosphatidylserine or phosphatidylcholine inhibited serine base-exchange, whereas the addition of phosphatidylethanolamine usually stimulated it. The effect of exogenous lipids also depended on molecular species; egg yolk phosphatidylcholine and dipalmitoyl phosphatidylcholine inhibited base-exchange whereas the effect of palmitoyl-oleoyl phosphatidylcholine depended on the incorporated amount. The degree of unsaturation also modulated the effect of phosphatidylethanolamine.

Transport and decarboxylation of liposomal phosphatidylserine: effect of cations.

Decarboxylation of liposomal phosphatidylserine by rat liver and Ehrlich ascites tumor mitochondria was taken as a measure of phospholipid transfer. The process was found to be greatly enhanced by the cytoplasmic fraction of rat liver containing nonspecific lipid transfer protein, but not by the cytoplasmic fraction from tumor cells. Divalent cations, like rat liver cytoplasmic fraction, also stimulated phosphatidylserine decarboxylation by facilitating the lipid association with mitochondria. In contrast, these cations, at 0.5-3 mM concentration, inhibited the cytoplasmic fraction-mediated phosphatidylserine transport. Monovalent cations were also inhibitory but at 20-150 mM concentration. However, they had no effect on phosphatidylserine decarboxylation in the absence of the cytoplasmic fraction. Further experiments with purified rat liver nonspecific lipid transfer protein and pyrene-labeled phosphatidylcholine and phosphatidylserine have shown that cations by neutralizing net negative charge on phospholipid donor vesicles decrease the interaction of protein with them and, in consequence, lower the rate of release of molecules to the water phase.

Regulation of liver base-exchange activity by acidic phospholipids.

Liver microsomes were enriched in liposomal acidic lipids by Ca(2+)-dependent fusion of liposomes at pH 7.0. The extent of fusion was monitored by the transfer of radioactive cholesteryl oleate. The enrichment of membranes in phosphatidylserine inhibited ethanolamine base-exchange, whereas the fusion with phosphatidylinositol inhibited both ethanolamine and serine base-exchange reactions. In contrast, these two phospholipids had scarce effects on choline base-exchange. Phosphatidic acid did not suppress any of the three base-exchange activities. Possible functional implications are discussed.

Effect of hyper- and hypothyroidism on phospholipid fatty acid composition and phospholipases activity in sarcolemma of rabbit cardiac muscle.

Lipid content and composition of fatty acids esterified to phospholipids of cardiac sarcolemma isolated from hyperthyroid, hypothyroid and control rabbits were analysed. Hyperthyroidism resulted in a significant reduction of the cholesterol to phospholipid molar ratio as compared to control animals, while hypothyroidism exerted the opposite effect. Complex changes in composition of phospholipid fatty acids observed in hyperthyroid state led to an elevation of the fatty acid unsaturation index over the control value. The unsaturation index value was, however, not affected in the hypothyroid state. Thyroxine hormone administration increased phospholipase A1 and decreased phospholipase A2 activity. The opposite effect was observed in thyreodectomized animals. The effect of changes in sarcolemmal bulk phospholipids upon thyroxine administration or deficiency on regulation of activity of membrane-bound enzymes is discussed.

Membrane lateral pressure as a modulator of glycerol-3-phosphate dehydrogenase activity.

Michaelis-Menten kinetics of glycerol-3-phosphate dehydrogenase activity in proteoliposomes from brown adipose tissue mitochondria with exogenously added phospholipids or cholesterol was measured. It was shown that changes in membrane lipid composition affected the membrane lateral pressure and therefore modulated the enzyme activity, namely Vmax value. Contrarily, changes in surface charge caused by minute amounts of phosphatidylserine or charged organic substances influenced only the apparent Km value. The role of bulk phospholipids in regulation of glycerol-3-phosphate dehydrogenase is discussed.