Effects of two different oral contraceptives on homocysteine metabolism in women with polycystic ovary syndrome

PURPOSE: This study was conducted to evaluate the effects of two different oral contraceptives (OCs) on homocysteine (Hcy) metabolism in 20 women with polycystic ovary syndrome (PCOS). METHODS: Women were randomly allocated to receive either the biphasic OC containing 40/30 mug ethynylestradiol (EE)+25/125 mug desogestrel (DSG; n=10) or the monophasic OC containing 35 mug EE and 2 mg cyproterone acetate (CPA; n=10). Investigations were performed before and after 6 months of treatment. Fasting vitamin B(12), folate, Hcy and insulin sensitivity (SI), and glucose utilization independent of insulin (Sg), by the minimal model method, were evaluated. RESULTS: Folate and vitamin B(12) were not significantly modified by either OC. EE/DSG decreased SI (2.53+/-0.35 vs. 1.68+/-0.45; p<.05), without modifying Hcy (9.54+/-0.7 micromol/L vs. 9.18+/-0.6 micromol/L). EE/CPA improved SI (1.47+/-0.38 vs. 3.27+/-0.48; p<.04) and decreased Hcy (9.8+/-1.9 micromol/L vs. 7.9+/-0.9 micromol/L; p<.05). This study indicates that in women with PCOS, EE/CPA, but not EE/DSG, improves IS and decreases fasting Hcy.     

Effect of ovarian suppression on glucose metabolism of young lean women with and without ovarian hyperandrogenism

Gonadal steroids are believed to influence glucose metabolism, oestrogens inducing an improvement and androgens or progestins a deterioration. At baseline and after 3 months of ovarian suppression with a gonadotrophin-releasing hormone analogue (GnRHa: goserelin depot 3.75 mg/28 days), glucose metabolism was evaluated in eight lean women affected by ovarian hyperandrogenism (PCOS) and six age-weight-matched non-hyperandrogenic women (controls) by using both an oral glucose tolerance test (75 g; OGTT) and the minimal model method. The latter method allows calculation of peripheral insulin sensitivity (Si) and glucose dependent glucose utilization (Sg). In PCOS, higher fasting concentrations (P < 0.05) of insulin and C-peptide, and lower Sg (P < 0.05) and Si (P < 0.01) were found. GnRHa did not significantly modify glucose metabolism of controls, while in women with PCOS it decreased fasting glucose (P < 0.05) and significantly increased Si (P < 0.03) up to control values. The present data indicate that strong suppression of ovarian activity improves Si in lean women with PCOS, while it is without relevant effects on glucose metabolism of non-hyperandrogenic women.     

Raloxifene does not modify insulin sensitivity and glucose metabolism in postmenopausal women

Insulin sensitivity (Si), glucose tolerance, and lipid metabolism were investigated in osteopenic postmenopausal women before and after 6 months of treatment with raloxifene (60 mg/d) or placebo. In a group of women (n = 34), glucose metabolism was evaluated by means of an oral glucose tolerance test (75 g). In another group of women (n = 24), Si and peripheral glucose utilization not dependent on insulin were evaluated by means of a frequently sampled iv glucose tolerance test associated with the minimal model method. No metabolic modification was observed in women receiving placebo. Raloxifene did not significantly modify high density lipoprotein-cholesterol and triglycerides, whereas it significantly decreased low density lipoprotein (LDL) cholesterol (4.84 +/- 0.34 mmol/liter vs. 3.83 +/- 0.49 mmol/liter; P = 0.014) and LDL/high density lipoprotein cholesterol ratio (3.21 +/- 0.31 mmol/liter vs. 2.46 +/- 0.44 mmol/liter; P = 0.012). Fasting levels and responses to the oral glucose tolerance test of glucose, insulin, C-peptide, and C-peptide/insulin were not modified by raloxifene. Similarly, raloxifene did not modify Si (4.22 +/- 4.1 vs. 5.13 +/- 1.75), or insulin (0.025 +/- 0.003 vs. 0.019 +/- 0.002). The present data show that in osteopenic postmenopausal women raloxifene reduces LDL levels but does not modify insulin sensitivity and glucose metabolism.     

Restoration of luteinizing hormone response to naloxone in postmenopausal women by chronic administration of the antidopaminergic drug veralipride

To determine whether antidopaminergic drug administration may modify endogenous opioid activity at the hypothalamic-pituitary level, the effects of naloxone infusion (1.6 mg/h for 4 h) on LH secretion were studied in six postmenopausal women before and after administration of the potent antidopaminergic drug veralipride for 20 days. Before veralipride administration, the naloxone infusion did not alter LH secretion. Chronic administration of veralipride resulted in a significant (P less than 0.01) decline in plasma LH levels. In addition, the naloxone infusion induced a significant (P less than 0.05) increase in plasma LH levels, which reached values similar to those before veralipride administration. These results demonstrate that in postmenopausal women the antidopaminergic drug veralipride can restore, at least in part, the activity of the endogenous opioid system. These findings suggest that endogenous opioid peptides may mediate the inhibitory effect exerted by chronic antidopaminergic drug administration on LH secretion in humans.     

Experimental evidence of memory-based foraging decisions in a large wild mammal

Many animals restrict their movements to a characteristic home range. This constrained pattern of space use is thought to result from the foraging benefits of memorizing the locations and quality of heterogeneously distributed resources. However, due to the confounding effects of sensory perception, the role of memory in home-range movement behavior lacks definitive evidence in the wild. Here, we analyze the foraging decisions of a large mammal during a field resource manipulation experiment designed to disentangle the effects of memory and perception. We parametrize a mechanistic model of spatial transitions using experimental data to quantify the cognitive processes underlying animal foraging behavior and to predict how individuals respond to resource heterogeneity in space and time. We demonstrate that roe deer (Capreolus capreolus) rely on memory, not perception, to track the spatiotemporal dynamics of resources within their home range. Roe deer foraging decisions were primarily based on recent experience (half-lives of 0.9 and 5.6 d for attribute and spatial memory, respectively), enabling them to adapt to sudden changes in resource availability. The proposed memory-based model was able to both quantify the cognitive processes underlying roe deer behavior and accurately predict how they shifted resource use during the experiment. Our study highlights the fact that animal foraging decisions are based on incomplete information on the locations of available resources, a factor that is critical to developing accurate predictions of animal spatial behavior but is typically not accounted for in analyses of animal movement in the wild.

Many animals, both territorial and nonterritorial, constrain their movements to a characteristic home range, an area that is typically much smaller than their movement abilities would allow (1). The ubiquity of this space-use pattern suggests that home ranges are adaptive and that a general mechanism underpins their emergence (2). In particular, home ranges are thought to result from the foraging benefits provided by spatial memory (3)—the process by which animals encode spatial relations (4).The role of spatial memory is particularly relevant when resources are spatially heterogeneous and temporally dynamic (5), making foraging a complex, spatiotemporal problem. Classic optimal foraging theory (6), as well as resource selection analyses (7), assume that animals have either no knowledge (i.e., a random forager), or perfect knowledge of the spatiotemporal patterns of resources (i.e., an omniscient forager). However, in reality, animal foraging decisions must rely on imperfect information (8) obtained from two sources: direct sensory perception, and memories of previous experiences at locations beyond the individual’s current perceptual range (4, 9).In this context, memory should be adaptive whenever retaining past site-specific information to predict the future occurrence and quality of key resources is more efficient than foraging relying on proximal mechanisms, such as area-restricted search and perception (3). Accordingly, foragers may not only benefit from memorizing spatial locations but also from tracking the profitability of previously-visited resources by means of an attribute memory (4). Such dynamic learning allows the forager to develop an expectation of resource quality from previous experience (10) and implies the discounting of old information (11, 12). In support of this argument, theoretical studies have demonstrated the foraging advantage of memory in spatially heterogeneous, predictable landscapes (13–15).Empirically, the benefits of memory for resource acquisition have been documented for several kinds of central-place foragers, in particular frugivorous bats (16, 17), hummingbirds (18), food-caching birds (19, 20), and bumblebees (21). Experimental evidence of memory-based foraging decisions in wild mammalian home ranges has been limited. The influence of memory and perception on the movement behavior of mammals has been inferred in several observational studies (22, 23); however, quantifying their respective influences on foraging decisions is challenging because both memory and perception can give rise to long-distance, goal-oriented movements. Field experiments have the potential to address this limitation by providing the level of control required to disentangle the effects of memory and perception (4, 10). In a rare field experiment on mammals, Janson showed that the home-range movements of a brown capuchin (Cebus apella) troop deviated from a perception-based movement model (24, 25); however, a mechanistic, quantitative understanding of how memory affects mammalian foraging movements is still lacking.In this study, we address this gap by formulating a memory-based model of spatial transitions to 1) characterize and quantify the cognitive processes involved in the foraging decisions of a large mammal, and 2) predict the observed patterns of response to a resource manipulation experiment. We performed our experiment on European roe deer (Capreolus capreolus). Roe deer are a particularly well-suited species for studying the interplay between cognitive processes and resource dynamics: as browser with limited fat reserves, roe deer exhibit a tight association between movement and resource dynamics (26), particularly during the winter months (i.e., at the time of our experiment) when food scarcity limits foraging performance, and the movements of roe deer are not affected by territoriality. In addition, because roe deer are solitary, their foraging decisions are expected to be primarily based on their individual, personal information (27).We fitted roe deer with Global Positioning System (GPS) telemetry collars at a site in the Eastern Italian Alps, and followed their movements during a transitory alteration of high-nutritional food accessibility at supplemental feeding sites (FS), located within their home range (n = 18 individuals, for a total of 25 animal-years; see Materials and Methods). The 6 wk experiment, conducted over 3 y, consisted of three 2 wk phases—pre-closure, closure, and post-closure—and was designed to disentangle the effects of memory and perception. During the closure phase, the food at the most-attended FS of each individual (hereafter referred to as manipulated, M) was rendered inaccessible by installing a physical barrier while maintaining food presence at the site (Fig. 1B). This ensured that sensory information on resource availability remained unaltered by the manipulation.Open in a separate windowFig. 1.Transitory changes in resource use patterns during the experiment. (A–C) Schematic representation of the experiment. High-nutritional food is accessible at M feeding sites (FS) during the pre- and post-closure phases (A and C, respectively), while it is present but inaccessible during the closure phase (B). Supplemental food is also present throughout the experiment at A FS. Roe deer can also access V. (D–F) Transition probabilities among the three resource types—V, M, and A—for pre-closure (as rates; n = 9,045 transitions; D), closure (as net changes in respect to pre-closure; n = 9,187; E), and post-closure (as net changes in respect to closure; n = 8,417; F). For the net changes, the color of the vertices indicates a decreased (red) or increased (blue) probability (significant changes are in bold). (G–I) Corresponding relative resource use, with vertical arrows illustrating the compensation pattern observed between the use of M and A.We characterized the temporal dynamics of roe deer foraging patterns during the experiment by quantifying the fraction of time each individual spent in the vicinity of their manipulated FS (M), at alternate FS available within the broader landscape (A), and in natural vegetation (V). We then developed a model describing the transition probabilities between states (M, A, and V) as a function of resource accessibility, resource preference, and cognitive processes, while controlling for environmental cues (illumination patterns and temperature). We evaluated three competing hypotheses concerning the cognitive mechanisms underlying the patterns of movement by roe deer during the experiment (Table 1): 1) Hypothesis 1 is a null hypothesis of omniscience-based movement, in which animals possess complete information on the spatiotemporal dynamics of resources. Under this hypothesis, we predicted that individuals would no longer visit M FS when forage is inaccessible (P1.1) and respond instantaneously to actual changes in resource accessibility (P1.2), irrespective of their previous experience. 2) Hypothesis 2 is a perception-based movement hypothesis in which animals use long-distance sensory cues to guide their foraging decisions. At the spatial scale of this experiment, in which FS are hundreds of meters apart, we assumed that, as in other large herbivores (28), roe deer would primarily rely on olfactory rather than visual perception because the presence of food at FS is not visible from afar. Since the manipulation did not alter the sensory information that can be perceived at long distances, we predicted that, under the perception hypothesis, the rate at which roe deer visited M FS would be constant throughout the experiment (P2.1) and that their foraging decisions should be independent of resource accessibility (P2.2). 3) Hypothesis 3 is a memory-based movement hypothesis in which animals rely on previous experience to guide foraging decisions. We predicted that, under this hypothesis, roe deer would decrease their visits to inaccessible FS (P3.1), conditional on experienced changes in resource accessibility (P3.2). We further predicted that the influence of previously visited FS on roe deer movement would slowly decrease with time since last visit (i.e., slow decay of spatial memory; P3.3) and that the expected value of FS would primarily rely on very recent experience (i.e., fast decay of attribute memory; P3.4). To evaluate hypothesis 3, we formulated a bicomponent memory model consisting of two forms of memory: a spatial memory (i.e., recollection of resource locations) and an attribute memory (i.e., recollection of the profitability at previously visited locations; sensu refs. 4 and 23). Further details on the mathematical formulations of the three above hypotheses can be found in the Materials and Methods. We fitted the three cognitive models for each individual separately, that is, the scale at which foraging decisions are taken, to evaluate the generality of the cognitive mechanisms used by roe deer (Results); we also fitted population-level models to summarize the relative importance of the underlying drivers (SI Appendix, section 5).Table 1.Hypotheses and corresponding predictions

Glucose metabolism and insulin resistance in women with polycystic ovary syndrome during therapy with oral contraceptives containing cyproterone acetate or desogestrel

Oral contraceptives slightly deteriorate insulin sensitivity. The present study investigated whether they may further unbalance the glucose metabolism of lean women with polycystic ovary syndrome (PCOS). Women with PCOS were assigned to receive for 6 months the biphasic association of 40/30 micro g ethinyl estradiol (EE) and 25/125 micro g desogestrel (DSG; n = 10) or the monophasic association of 35 micro g EE and 2 mg cyproterone acetate (CPA; n = 10). Glucose tolerance was investigated by an oral glucose tolerance test (OGTT). Glucose utilization dependent [insulin sensitivity (SI)] or independent (Sg) of insulin was investigated by the minimal model method applied to a frequently sampled iv glucose tolerance test. EE/DSG increased the response of C peptide to OGTT (1413 +/- 113 vs. 2053 +/- 213 area under the curve; P < 0.009) and the C peptide/insulin ratio (0.085 +/- 0.01 vs. 0.134 +/- 0.01 area under the curve; P < 0.003). It also increased the Sg (0.026 +/- 0.002 vs. 0.034 +/- 0.003; P < 0.04) and decreased the SI (2.40 +/- 0.26 vs. 1.68 +/- 0.27; P < 0.01). EE/CPA did not modify responses to OGTT of glucose, insulin, C peptide, or C peptide/insulin ratio. It did not modify Sg and significantly increased SI (1.47 +/- 0.38 vs. 3.27 +/- 0.48; P < 0.04). The present study indicates that EE/CPA improves SI, whereas EE/DSG impairs SI, but improves insulin clearance. The long-term metabolic effects of these two compounds on women with PCOS require further investigations.     

Effects of low- or high-dose hormone therapy on fasting and post-methionine homocysteine levels in postmenopausal women.

OBJECTIVE: To evaluate the effect of two different hormone therapy (HT) doses on fasting and post-methionine homocysteine levels, an independent risk factor for cardiovascular and thromboembolic diseases. METHODS: Forty-eight women in natural postmenopause randomly received calcium 1 mg/day (control group; n = 12) or calcium plus low dose (1 mg estradiol plus 0.5 mg norethisterone; n = 18) or high dose (2 mg estradiol plus 1 mg norethisterone; n = 18) HT in a 6-month randomized, controlled, prospective study. RESULTS: Folate levels did not vary in any group, while levels of vitamin B12 significantly decreased after low- (-12.2 +/- 6.6%; p < 0.04) or high-dose HT (-13.9 +/- 6.1%; p < 0.01). Fasting homocysteine was reduced by either HT dose in a way that was inversely related to pretreatment homocysteine levels (-0.675x; r = 0.644; p < 0.0001). Modification of post-load homocysteine increase was influenced by the HT dose and inversely related to the homocysteine response to methionine observed at baseline. The regression slope observed with the low-dose HT (-1.637x; r = 0.57; p < 0.02) was significantly steeper (p < 0.001) than that observed with the high-dose HT (-0.304x; r = 0.554; p < 0.03) dose. CONCLUSIONS: Low- or high-dose HT similarly influences fasting homocysteine levels. Low-dose HT seems to be more effective than high-dose HT in reducing the post-methionine homocysteine increase.