Lifestyle intervention up-regulates gene and protein levels of molecules involved in insulin signaling in the endometrium of overweight/obese women with polycystic ovary syndrome.

STUDY QUESTION: Does lifestyle intervention aiming at weight loss influence endometrial insulin signaling in overweight/obese women with polycystic ovary syndrome (PCOS)? SUMMARY ANSWER: Lifestyle intervention up-regulates, both at the mRNA and protein levels, components of insulin signaling in the endometrium of overweight/obese PCOS women, in relation to an improved menstrual pattern. WHAT IS KNOWN ALREADY: PCOS is a multifactorial endocrine disorder diagnosed by two of the following three criteria: chronic anovulation, hyperandrogenism and polycystic ovaries. Many women with PCOS also have insulin resistance and obesity. The syndrome is furthermore associated with endometrial cancer and possible alterations in endometrial function and receptivity. STUDY DESIGN, SIZE, DURATION: This study assessed the effects of a combined diet and exercise lifestyle intervention for 3 months. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 20 overweight/obese PCOS women with anovulation, hyperandrogenism and polycystic ovaries were subjected to a combined diet and exercise program for 3 months. Ten body mass index (BMI)-matched regularly menstruating overweight/obese controls, nine normal-weight PCOS women and ten normal-weight controls were also included in the study. In an academic clinical setting, women were examined in mid-follicular phase for endocrine assessment and determination of endometrial levels of mRNA and immunohistochemical staining of insulin signaling molecules (the insulin receptor, insulin receptor substrate-1 (IRS1) and glucose transporter (GLUT) 1 and 4). MAIN RESULTS AND THE ROLE OF CHANCE: Women with PCOS exhibited lower levels of IRS1 (P < 0.01) and GLUT4 (P < 0.01) mRNA in their proliferative endometrium than BMI-matched controls. After lifestyle intervention, weight loss averaged 4.7% and the menstrual pattern improved in 65% of the overweight/obese women with PCOS. Levels of IRS1 (P < 0.01) and GLUT1 (P < 0.05) mRNA were significantly up-regulated in the endometrium of those women with improved menstrual function, as were the protein expression levels of pY612IRS1 (the activated IRS1 form, P < 0.05), pS312IRS1 (the inhibitory form of IRS1, P < 0.05) and GLUT1 (P < 0.05). Improvement in the menstrual function of women in the obese/overweight group following the lifestyle intervention was positively correlated with the increase in the endometrial level of IRS1 mRNA (r = 0.63, P < 0.01) and negatively correlated with the change in BMI (r = -0.50, P < 0.05). LIMITATIONS, REASONS FOR CAUTION: The number of women in each group was limited, although the power calculation indicated that the number of patients subjected to the lifestyle intervention was sufficient. WIDER IMPLICATIONS OF THE FINDINGS: We propose that up-regulation of endometrial IRS1 and GLUT1 in overweight/obese women with PCOS following lifestyle intervention improves the glucose homeostasis and thereby restores the functioning of the endometrium in these women. STUDY FUNDING/COMPETING INTEREST(S): This study was supported financially by the Swedish Research Council (A.L.H., 20324), Karolinska Institutet and the Stockholm County Council. None of the authors has any conflict of interest to declare.

Effects of oral contraceptives on diurnal profiles of insulin, insulin-like growth factor binding protein-1, growth hormone and cortisol in endurance athletes with menstrual disturbance.

BACKGROUND: Menstrual disturbances in female athletes are often explained as a consequence of energy deficiency. Oral contraceptive (OC) treatment may have favorable metabolic effects. We evaluated effects of OCs on diurnal secretions of insulin, insulin-like growth factor binding protein 1 (IGFBP-1), growth hormone (GH) and cortisol in relation to changes in body composition in athletes with menstrual disturbance compared with regularly menstruating athletes and controls. METHODS: Age- and BMI-matched groups of endurance athletes with menstrual disturbance (OAM, n = 9) and regularly cycling athletes (RM, n = 8) and sedentary controls (CTRL, n = 8) were examined, and hormone levels measured, before and after 8 months of treatment with a low-dose combined OC (30 microg ethinyl estradiol + 150 microg levonorgestrel). RESULTS: Before OC treatment, the diurnal profile of insulin was lower (P < 0.01) and levels of IGFBP-1 (P < 0.05) and cortisol (P < 0.05) were higher in OAM athletes than in CTRL, whereas GH secretion was higher than in RM athletes (P < 0.05). After treatment, diurnal secretions of these hormones were similar between groups with an increase of IGFBP-1 in the regularly menstruating subjects only (P < 0.001). OC treatment increased body fat mass in OAM athletes (P < 0.01 versus baseline). The change in total fat mass correlated positively with pretreatment diurnal levels of GH (r(s) = 0.67, P < 0.01) and cortisol (r(s) = 0.64, P < 0.01). CONCLUSIONS: OC treatment in endurance athletes with menstrual disturbance increases body fat mass and results in diurnal levels of insulin, IGFBP-1, GH and cortisol that are comparable to those in regularly menstruating subjects. These results suggest that OCs improve metabolic balance in OAM athletes.