Taking aim at the perceptual side of motor learning: exploring how explicit and implicit learning encode perceptual error information through depth vision.

Motor learning in visuomotor adaptation tasks results from both explicit and implicit processes, each responding differently to an error signal. Although the motor output side of these processes has been extensively studied, the visual input side is relatively unknown. We investigated if and how depth perception affects the computation of error information by explicit and implicit motor learning. Two groups of participants made reaching movements to bring a virtual cursor to a target in the frontoparallel plane. The Delayed group was allowed to reaim and their feedback was delayed to emphasize explicit learning, whereas the camped group received task-irrelevant clamped cursor feedback and continued to aim straight at the target to emphasize implicit adaptation. Both groups played this game in a highly detailed virtual environment (depth condition), leveraging a cover task of playing darts in a virtual tavern, and in an empty environment (no-depth condition). The delayed group showed an increase in error sensitivity under depth relative to no-depth. In contrast, the clamped group adapted to the same degree under both conditions. The movement kinematics of the delayed participants also changed under the depth condition, consistent with the target appearing more distant, unlike the Clamped group. A comparison of the delayed behavioral data with a perceptual task from the same individuals showed that the greater reaiming in the depth condition was consistent with an increase in the scaling of the error distance and size. These findings suggest that explicit and implicit learning processes may rely on different sources of perceptual information.NEW & NOTEWORTHY We leveraged a classic sensorimotor adaptation task to perform a first systematic assessment of the role of perceptual cues in the estimation of an error signal in the 3-D space during motor learning. We crossed two conditions presenting different amounts of depth information, with two manipulations emphasizing explicit and implicit learning processes. Explicit learning responded to the visual conditions, consistent with perceptual reports, whereas implicit learning appeared to be independent of them.

Stereovision for action reflects our perceptual experience of distance and depth.

Binocular vision is widely recognized as the most reliable source of 3D information within the peripersonal space, where grasping takes place. Since grasping is normally successful, it is often assumed that stereovision for action is accurate. This claim contradicts psychophysical studies showing that observers cannot estimate the 3D properties of an object veridically from binocular information. In two experiments, we compared a front-to-back grasp with a perceptual depth estimation task and found that in both conditions participants consistently relied on the same distorted 3D representation. The subjects experienced (a) compression of egocentric distances: objects looked closer to each other along the z-axis than they were, and (b) underconstancy of relative depth: closer objects looked deeper than farther objects. These biases, which stem from the same mechanism, varied in magnitude across observers, but they equally affected the perceptual and grasping task of each subject. In a third experiment, we found that the visuomotor system compensates for these systematic errors, which are present at planning, through online corrections allowed by visual and haptic feedback of the hand. Furthermore, we hypothesized that the two phenomena would give rise to estimates of the same depth interval that are geometrically inconsistent. Indeed, in a fourth experiment, we show that the landing positions of the grasping digits differ systematically depending on whether they result from absolute distance estimates or relative depth estimates, even when the targeted spatial locations are identical.

Life-style and metformin for the prevention of endometrial pathology in postmenopausal women.

In western women, the endometrium is frequently exposed, even after menopause, to the endogenous hormonal stimulation. Such a stimulation increases the risk of pathologic conditions such as endometrial hyperplasia and type I (endometrioid) endometrial adenocarcinoma. Metabolic syndrome, obesity, insulin resistance and type II diabetes promote the endometrial stimulation, and are recognized risk factors for endometrial cancer. Furthermore, chronic hyperinsulinemia linked both to obesity and metabolic syndrome influences endometrial proliferation through direct and indirect actions. Intentional weight loss, calorie restriction and physical activity are associated with a reduced risk of the endometrial pathology. Biological mechanisms include reduction in insulin and sex steroid hormone levels. In addition to life-style modifications, the antidiabetic metformin may be proposed as preventive agent. Metformin reduces the metabolic syndrome, lowers insulin and testosterone levels in postmenopausal women, and it is a potent inhibitor of endometrial cancer cell proliferation.

Kinematic markers of skill in first-person shooter video games.

Video games present a unique opportunity to study motor skill. First-person shooter (FPS) games have particular utility because they require visually guided hand movements that are similar to widely studied planar reaching tasks. However, there is a need to ensure the tasks are equivalent if FPS games are to yield their potential as a powerful scientific tool for investigating sensorimotor control. Specifically, research is needed to ensure that differences in visual feedback of a movement do not affect motor learning between the two contexts. In traditional tasks, a movement will translate a cursor across a static background, whereas FPS games use movements to pan and tilt the view of the environment. To this end, we designed an online experiment where participants used their mouse or trackpad to shoot targets in both visual contexts. Kinematic analysis showed player movements were nearly identical between contexts, with highly correlated spatial and temporal metrics. This similarity suggests a shared internal model based on comparing predicted and observed displacement vectors rather than primary sensory feedback. A second experiment, modeled on FPS-style aim-trainer games, found movements exhibited classic invariant features described within the sensorimotor literature. We found the spatial metrics tested were significant predictors of overall task performance. More broadly, these results show that FPS games offer a novel, engaging, and compelling environment to study sensorimotor skill, providing the same precise kinematic metrics as traditional planar reaching tasks.

Explicit and implicit depth-cue integration: Evidence of systematic biases with real objects.

In previous studies using VR, we found evidence that 3D shape estimation agrees to a superadditivity rule of depth-cue combination, by which adding depth cues leads to greater perceived depth and, in principle, to depth overestimation. Superadditivity can be quantitatively accounted for by a normative theory of cue integration, via adapting a model termed Intrinsic Constraint (IC). As for its qualitative nature, it remains unclear whether superadditivity represents the genuine readout of depth-cue integration, as predicted by IC, or alternatively a byproduct of artificial virtual displays, because they carry flatness cues that can bias depth estimates in a Bayesian fashion, or even just a way for observers to express that a scene "looks deeper" with more depth cues by explicitly inflating their depth judgments. In the present study, we addressed this question by testing whether the IC model's prediction of superadditivity generalizes to real world settings. We asked participants to judge the perceived 3D shape of cardboard prisms through a matching task. To control for the potential interference of explicit reasoning, we also asked participants to reach-to-grasp the same objects and we analyzed the in-flight grip size throughout the reaching. We designed a novel technique to carefully control binocular and monocular 3D cues independently, allowing to add or remove depth information seamlessly. Even with real objects, participants exhibited a clear superadditivity effect in both tasks. Furthermore, the magnitude of this effect was accurately predicted by the IC model. These results confirm that superadditivity is an inherent feature of depth estimation.

Does depth-cue combination yield identical biases in perception and grasping?

Grasping critically depends on stereo information. We previously found that binocular disparities yield a distorted visual space, in which objects close to the observer are grasped and perceived as if they were more elongated than farther objects. Such lack of shape constancy results from the inaccurate estimate of the viewing distance, which affects the estimated depth-to-width ratio of an object. This is because (1) depth from binocular disparities scales with the square of the distance and (2) width from retinal size scales linearly with distance. Conversely, depth from monocular cues (i.e., motion and texture gradients) scales linearly with distance, hence the overall shape from these signals should not be affected by errors in egocentric estimates of object location. We therefore reasoned that adding these cues to stereo information should improve shape constancy. Contrary to expectations, in four experiments we found that stereo-texture and stereo-motion stimuli appeared even more distorted than stereo stimuli. More remarkably, results revealed that grasping execution showed identical biases, which were corrected only late in the movement through online control mechanisms, but only if both grasping digits could be visually guided on their respective contact locations. On the contrary, when the index was occluded by the object, biases in shape estimation continued to affect grasping execution until movement completion. Moreover, while the initial part of the grasp showed evidence of collision avoidance, a control experiment suggested that the above biases could have emerged as early as at movement planning, consistent with previous evidence. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Does visuomotor adaptation contribute to illusion-resistant grasping?

Do illusory distortions of perceived object size influence how wide the hand is opened during a grasping movement? Many studies on this question have reported illusion-resistant grasping, but this finding has been contradicted by other studies showing that grasping movements and perceptual judgments are equally susceptible. One largely unexplored explanation for these contradictions is that illusion effects on grasping can be reduced with repeated movements. Using a visuomotor adaptation paradigm, we investigated whether an adaptation model could predict the time course of Ponzo illusion effects on grasping. Participants performed a series of trials in which they viewed a thin wooden target, manually reported an estimate of the target's length, then reached to grasp the target. Manual size estimates (MSEs) were clearly biased by the illusion, but maximum grip apertures (MGAs) of grasping movements were consistently accurate. Illusion-resistant MGAs were observed immediately upon presentation of the illusion, so there was no decrement in susceptibility for the adaptation model to explain. To determine whether online corrections based on visual feedback could have produced illusion-resistant MGAs, we performed an exploratory post hoc analysis of movement trajectories. Early portions of the illusion effect profile evolved as if they were biased by the illusion to the same magnitude as the perceptual responses (MSEs), but this bias was attenuated prior to the MGA. Overall, this preregistered study demonstrated that visuomotor adaptation of grasping is not the primary source of illusion resistance in closed-loop grasping.

Differential effects of various progestogens on metabolic risk factors for breast cancer.

Biological and epidemiological findings suggest that metabolic factors - insulin, insulin-like growth factor-I (IGF-I) and sex hormone-binding globulin (SHBG) - are involved in the development and promotion of breast cancer. Estrogens, particularly if administered orally, counteract metabolic factors that increase breast cancer risk, i.e. they reduce insulin and IGF-I and increase SHBG. This could contribute toward explaining epidemiological data showing that unopposed oral estrogens do not increase breast cancer risk, or do so only modestly. In contrast to natural progesterone and progesterone-derived progestins, progestins endowed with androgenic (or glucocorticoid) activity negatively influence these metabolic factors, counteracting the favorable effects of estrogens. While most biological and epidemiological findings suggest that natural progesterone does not augment breast cancer risk, available data show an increased risk with synthetic progestins - with the possible exception of progesterone-derived dydrogesterone. Different mechanisms for different progestins could possibly be involved. Differences from progesterone with regard to pharmacokinetics and pharmacodynamics, potency, interaction with the two isoforms of the progesterone receptor, and binding to other steroid receptors could all be relevant. These remain theoretical speculations for the time being, but the possibility that some progestins increase breast cancer risk through their negative influence on metabolic factors cannot be rejected.

Adaptation effects in grasping the Müller-Lyer illusion.

Recent results have shown that effects of pictorial illusions in grasping may decrease over the course of an experiment. This can be explained as an effect of sensorimotor learning if we consider a pictorial size illusion as simply a perturbation of visually perceived size. However, some studies have reported very constant illusion effects over trials. In the present paper, we apply an error-correction model of adaptation to experimental data of N=40 participants grasping the Müller-Lyer illusion. Specifically, participants grasped targets embedded in incremental and decremental Müller-Lyer illusion displays in (1) the same block in pseudo-randomised order, and (2) separate blocks of only one type of illusion each. Consistent with predictions of our model, we found an effect of interference between the two types when they were presented intermixed, explaining why adaptation rates may vary depending on the experimental design. We also systematically varied the number of object sizes per block, which turned out to have no effect on the rate of adaptation. This was also in accordance with our model. We discuss implications for the illusion literature, and lay out how error-correction models can explain perception-action dissociations in some, but not all grasping-of-illusion paradigms in a parsimonious and plausible way, without assuming different illusion effects.

Metformin-induced ablation of microRNA 21-5p releases Sestrin-1 and CAB39L antitumoral activities.

Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer.

Pregnancy, progesterone and progestins in relation to breast cancer risk.

In the last two decades the prevailing opinion, supported by the "estrogen augmented by progesterone" hypothesis, has been that progesterone contributes to the development of breast cancer (BC). Support for this opinion was provided by the finding that some synthetic progestins, when added to estrogen in hormone replacement therapy (HRT) for menopausal complaints, increase the BC risk more than estrogen alone. However, recent findings suggest that both the production of progesterone during pregnancy and the progesterone endogenously produced or exogenously administered outside pregnancy, does not increase BC risk, and could even be protective. The increased BC risk found with the addition of synthetic progestins to estrogen in HRT seems in all likelihood due to the fact that these progestins (medroxyprogesterone acetate and 19-nortestosterone-derivatives) are endowed with some non-progesterone-like effects which can potentiate the proliferative action of estrogens. The use of progestational agents in pregnancy, for example to prevent preterm birth, does not cause concern in relation to BC risk.

Progestins and progesterone in hormone replacement therapy and the risk of breast cancer.

Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.

Polyunsaturated fatty acids (PUFAs) might reduce hot flushes: an indication from two controlled trials on soy isoflavones alone and with a PUFA supplement.

OBJECTIVES: To investigate the effect on hot flushes of a soy isoflavone extract alone (Study A) and with the addition of a supplement of polyunsaturated fatty acids, PUFAs (Study B). METHODS: Subjects were postmenopausal women (29 in Study A, 28 in Study B) with more than five troublesome hot flushes per day. Both studies were double-blind randomized placebo-controlled trials with cross-over design, of 24-week duration. After a 2-week observation period, they were randomized to receive two capsules per day providing 60mg of isoflavones or placebo for 12 weeks; thereafter, women who had taken isoflavones were given placebo for a second 12-week period, and vice-versa. Women in the Study B were given also two capsules per day containing a PUFA supplement for the entire 24-week test period. RESULTS: Both studies showed the isoflavone extract to have no greater efficacy on hot flushes than the placebo. During the 24 weeks of the Study B there was a progressive and highly significant reduction in the number of hot flushes, independent of whether the women had begun with isoflavones or with placebo. CONCLUSION: In these two trials the isoflavone extract did not show greater efficacy on the hot flushes than the placebo. The reduction of hot flushes observed in the Study B might be due to the PUFA supplement. PUFAs, particularly Omega (Omega) 3-fatty acids, could reduce hot flushes through their influence on neuronal membranes and/or the modulation of the neurotransmitter function and the serotoninergic system. Studies specifically designed to document the action of PUFAs on hot flushes would be welcome.

Differential effects of progestins on the circulating IGF-I system.

OBJECTIVE: Circulating insulin-like growth factor-I (IGF-I) is mainly produced by the liver under GH stimulation and is influenced by nutrition and insulin. IGF-I bioavailability is regulated by interactions with specific binding proteins (IGFBPs). The objective of this paper is to review available data on modifications of the IGF-I system in menopausal women during HRT, with particular attention on the differential effects of progestins. METHOD: All available reports on the effects of different forms of HRT have been taken into account. RESULTS: Available data suggest that different kinds of HRT have different effect on the IGF-I system, depending on route of administration, oestrogen dose, basal IGF-I values and type of progestin. Oestrogen administration (oestrogen replacement therapy (ERT)) reduces circulating IGF-I mainly through a hepatocellular effect. The decrease is sharper when oral ERT is used (first pass hepatic effect) and in women with higher basal IGF-I levels. The progestins endowed with androgenic effects--the 19-nortestosterone derivatives and, to a lesser extent, medroxyprogesterone acetate (MPA)--tend to reverse the IGF-I decrease induced by oral oestrogens. In contrast, progestins devoid of androgen-like hepatocellular and metabolic actions (e.g. dydrogesterone) do not interfere with the IGF-I decrease induced by oral oestrogens. Data on the effect of ERT on IGFBP-3 level are not consistent. Oral ERT, via hepatocellular actions (amplified by the first pass hepatic effect) causes a two to three-fold increase in IGFBP-1 levels. Androgenic progestins oppose the IGFBP-1 increase induced by oral oestrogens. Data on the effect of ERT and different progestins on the level of free IGF-I are scant and inconsistent. CONCLUSION: Even if some aspects need clarification, available data demonstrate that different progestins have differential effects on the circulating IGF-I system.

Positive effects on cardiovascular and breast metabolic markers of oral estradiol and dydrogesterone in comparison with transdermal estradiol and norethisterone acetate.

OBJECTIVES: To assess differences in two sequential combined hormone replacement therapy (HRT) products on selected cardiovascular and breast metabolic markers. The products were different concerning the route of administration of estradiol and its combined progestin, either oral or transdermal, and the androgenic properties of progestogens, respectively, dydrogesterone and norethisterone acetate. METHODS: One hundred and nineteen healthy non-hysterectomized postmenopausal women were included in this open, multi-center, two parallel group trial. They were randomized to a treatment of six 28-day cycles with oral estradiol sequentially combined with dydrogesterone (oE2/D10) or a sequential combination patch of estradiol plus norethisterone acetate (tdE/NETA). At baseline and after six cycles the high-density lipoprotein cholesterol (HDL-C), the sex hormone binding globulin (SHBG) and the total insulin-like growth factor-I (IGF-I) blood levels were determined by a central laboratory. A total of 89 women were compliant to the protocol. RESULTS: After six cycles, a statistically significant difference (P<0.001) concerning HDL-C, SHBG and IGF-I levels was found between the two treatment groups. The HDL-C levels were increased in the oE2/D10 group and decreased in the tdE/NETA group, with a final difference of about 0.3 mmol/l. The oE2/D10 treatment induced a sharp increase (about 57 mmol/l) in SHBG levels. IGF-I levels decreased with both the products, but the difference in favor of the oE2/D10 treatment was of about 30 ng/ml. Moreover, patients on tdE/NETA with an IGF-I baseline value below the median showed an increase. CONCLUSION: Oral estradiol sequentially combined with dydrogesterone, a non-androgenic progestogen, induced positive changes of some cardiovascular (HDL-C) and breast (SHBG and IGF-I) metabolic markers. These effects were significantly different from those obtained with a transdermal estradiol associated to an androgenic progestogen.

Classification and pharmacology of progestins.

Besides the natural progestin, progesterone, there are different classes of progestins, such as retroprogesterone (i.e. dydrogesterone), progesterone derivatives (i.e. medrogestone) 17alpha-hydroxyprogesterone derivatives (i.e. chlormadinone acetate, cyproterone acetate, medroxyprogesterone acetate, megestrol acetate), 19-norprogesterone derivatives (i.e. nomegestrol, promegestone, trimegestone, nesterone), 19-nortestosterone derivatives norethisterone (NET), lynestrenol, levonorgestrel, desogestrel, gestodene, norgestimate, dienogest) and spironolactone derivatives (i.e. drospirenone). Some of the synthetic progestins are prodrugs, which need to be metabolized to become active compounds. Besides the progestogenic effect, which is in common for all progestins, there is a wide range of biological effects, which are different for the various progestins and have to be taken into account, when medical treatment is considered.

Metformin decreases circulating androgen and estrogen levels in nondiabetic women with breast cancer.

INTRODUCTION: Diabetic patients treated with metformin have a lower risk of developing BC or a better BC prognosis. Metformin might reduce cancer growth through direct antiproliferative effects or through indirect mechanisms, particularly the reduction of insulin. In a randomized study on nondiabetic BC patients in natural menopause with high testosterone levels, we observed a significant decrease in insulin and in testosterone levels with metformin 1500 mg/d compared with 1000 mg/d. We present the results of a new analysis of our study on the effect of metformin on the bioavailability of sex hormones. PATIENTS AND METHODS: One hundred twenty-four eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months continued the study using 1000 mg/d for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose to 1500 mg/d, and the other group continued with 1000 mg/d. RESULTS: Ninety-six women completed the study, 43 receiving metformin 1500 mg/day, and 53 receiving 1000 mg/day. The women receiving 1500 mg/d showed a greater and significant reduction of free testosterone (-29%) and estradiol (-38%), a borderline significant reduction of estrone and insulin-like growth factor-1, and a nonsignificant reduction of androstenedione. They also showed a nonsignificant increase of dehydroepiandrosterone sulfate. CONCLUSION: Metformin does not interfere with the production of dehydroepiandrosterone sulfate. Besides, it decreases estradiol levels, basically through the reduction of testosterone. These hormonal changes might have clinical relevance.

Effect of different doses of metformin on serum testosterone and insulin in non-diabetic women with breast cancer: a randomized study.

UNLABELLED: This is a randomized controlled trial to test the effect of different doses of metformin in patients with breast cancer and without diabetes, with the aim of modifying the hormonal and metabolic parameters linked to breast cancer prognosis. Analysis of the results suggest that the dose of 1500 mg/d of metformin causes a significant reduction of insulin and testosterone serum levels. BACKGROUND: Serum levels of insulin and testosterone may affect both breast cancer (BC) incidence and prognosis. Metformin reduces hyperglycemia and insulin levels in patients with diabetes. In women without diabetes and with polycystic ovary syndrome, metformin lowers both insulin and testosterone levels. Patients with diabetes who are treated with metformin showed a lower risk of cancer; a protective effect of metformin also was observed for BC. Recently, studies on metformin use for prevention or treatment of BC have been proposed in patients who are not diabetic. The aim of the present study was to test the effect of different doses of metformin on serum levels of insulin and testosterone in those postmenopausal patients with breast cancer and without diabetes who have basal testosterone levels ≥0.28 ng/mL (median value). PATIENTS AND METHODS: A total of 125 eligible women were initially invited to take metformin 500 mg/d for 3 months. The 108 women who completed the first 3 months were invited to continue the study with metformin 1000 mg/d (500 mg twice a day [b.i.d.]) for 1 month. The women were then randomized into 2 groups, and, for the subsequent 5 months, 1 group increased the dose by taking metformin 1500 mg/d (500 mg 3 times a day [t.i.d.]), and the other group continued with metformin 1000 mg /d (500 [b.i.d.]). RESULTS: A total of 96 women completed the study: 43 women received 1500 mg/d, and 53 women received 1000 mg/d. The women who took 1500 mg/d showed a significant reduction of insulin level, HOMA-IR index (homeostasis model assessment-insulin resistance index), testosterone level, and free androgen index compared with women treated with 1000 mg/d. After treatment with 1500 mg/d, the insulin level decreased by 25% and the testosterone level decreased by 23%. CONCLUSION: Both these changes might have a prognostic importance.