Effects of metformin on spontaneous and clomiphene-induced ovulation in the polycystic ovary syndrome. Effects of d-chiro-inositol in lean women with the polycystic ovary syndrome. Insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator correlates with insulin sensitivity in women with polycystic ovary syndrome. Metformin therapy increases insulin-stimulated release of D-chiro-inositol-containing inositolphosphoglycan mediator in women with polycystic ovary syndrome. Uncoupling between insulin and release of a D-chiro-inositol-containing inositolphosphoglycan mediator of insulin action in obese women With polycystic ovary syndrome.
BACKGROUND Obese women with the polycystic ovary syndrome are relatively unresponsive to the induction of ovulation by clomiphene . We hypothesized that reducing insulin secretion by administering metformin would increase the ovulatory response to clomiphene . METHODS We performed oral glucose-tolerance tests before and after the administration of 500 mg of metformin or placebo three times daily for 35 days in 61 obese women with the polycystic ovary syndrome . Women who did not ovulate spontaneously were then given 50 mg of clomiphene daily for five days while continuing to take metformin or placebo .  Serum progesterone was measured on days 14 , 28 , 35 , 44 , and 53 , and ovulation was presumed to have occurred if the concentration exceeded 8 ng per milliliter ( 26 nmol per liter ) on any of these days . RESULTS Twenty-one women in the metformin group and 25 women in the placebo group were given clomiphene because they did not ovulate spontaneously during the first phase of the study . Among the 21 women given metformin plus clomiphene , the mean ( + /-SE ) area under the serum insulin curve after oral glucose administration decreased from 6745+/-2021 to 3479+/-455 microU per milliliter per minute ( 40.5+/-12.1 to 20.9+/-2.7 nmol per liter per minute , P=0.03 ) , but it did not change significantly in the 25 women given placebo plus clomiphene . Nineteen of the 21 women ( 90 percent ) who received metformin plus clomiphene  ovulated ( mean peak serum progesterone concentration , 23.8+/-3.4 ng per milliliter [ 7.6+/-10.9 nmol per liter ] ) . Two of the 25 women ( 8 percent ) who received placebo plus clomiphene  ovulated ( P<0.001 ) . Overall , 31 of the 35 women ( 89 percent ) treated with metformin  ovulated spontaneously or in response to clomiphene  , as compared with 3 of the 26 women ( 12 percent ) treated with placebo . CONCLUSIONS The ovulatory response to clomiphene can be increased in obese women with the polycystic ovary syndrome by decreasing insulin secretion with metformin OBJECTIVE To determine whether the administration of D-chiro-inositol , a putative insulin-sensitizing drug , would affect the concentration of circulating insulin , the levels of serum and rogens , and the frequency of ovulation in lean women with the polycystic ovary syndrome . METHODS In 20 lean women ( body mass index , 20.0 to 24.4 kg/m 2 ) who had the polycystic ovary syndrome , treatment was initiated with either 600 mg of D-chiro-inositol or placebo orally once daily for 6 to 8 weeks . We performed oral glucose tolerance tests and measured serum sex steroids before and after therapy . To monitor for ovulation , we determined serum progesterone concentrations weekly . RESULTS In the 10 women given D-chiro-inositol , the mean ( + /- st and ard error ) area under the plasma insulin curve after oral administration of glucose decreased significantly from 8,343 + /- 1,149 mU/mL per min to 5,335 + /- 1,792 mU/mL per min in comparison with no significant change in the placebo group ( P = 0.03 for difference between groups ) . Concomitantly , the serum free testosterone concentration decreased by 73 % from 0.83 + /- 0.11 ng/dL to 0.22 + /- 0.03 ng/dL , a significant change in comparison with essentially no change in the placebo group ( P = 0.01 ) . Six of the 10 women ( 60 % ) in the D-chiro-inositol group ovulated in comparison with 2 of the 10 women ( 20 % ) in the placebo group ( P = 0.17 ) . Systolic ( P = 0.002 ) and diastolic ( P = 0.001 ) blood pressures , as well as plasma triglyceride concentrations ( P = 0.001 ) , decreased significantly in the D-chiro-inositol group in comparison with the placebo group , in which these variables either increased ( blood pressure ) or decreased minimally ( triglycerides ) . CONCLUSION We conclude that , in lean women with the polycystic ovary syndrome , D-chiro-inositol reduces circulating insulin , decreases serum and rogens , and ameliorates some of the metabolic abnormalities ( increased blood pressure and hypertriglyceridemia ) of syndrome Some actions of insulin are mediated by inositolphosphoglycan ( IPG ) mediators . Deficient release of a putative D-chiro-inositol-containing ( DCI ) IPG mediator may contribute to insulin resistance in women with polycystic ovary syndrome ( PCOS ) . Previously , we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS . However , whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown . We conducted a r and omized controlled trial of DCI supplementation vs placebo in 11 women with PCOS who were assessed at 2 time points 6 weeks apart .  Plasma DCI , DCI-IPG release during oral glucose tolerance test ( AUC(DCI-IPG ) ) , and insulin sensitivity ( S(i ) ) by frequently sample d intravenous glucose tolerance test were assessed at baseline and end of study . The study was terminated early because of a sudden unavailability of the study drug . However , in all subjects without regard to treatment assignment , there was a positive correlation between the change in AUC(DCI-IPG)/AUC(insulin ) ratio and the change in S(i ) during the 6-week period ( r = 0.69 , P = .02 ) , which remained significant after adjustment for body mass index ( P = .022 ) and after further adjustment for body mass index and treatment allocation ( P = .0261 ) . This suggests that , in women with PCOS , increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity . The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS Some actions of insulin are mediated by putative inositolphosphoglycan mediators , and a deficiency in D-chiro-inositol-containing inositolphosphoglycan ( DCI-IPG ) may contribute to insulin resistance in women with polycystic ovary syndrome ( PCOS ) . Furthermore , similar effects of DCI and metformin , an insulin-sensitizing drug , have been demonstrated in PCOS women . To determine whether metformin improves insulin actions by increasing biologically active DCI-IPG in women with PCOS , we analyzed DCI-IPG during an oral glucose tolerance test in 19 obese women with PCOS before and after 4 - 8 wk of metformin or placebo .  After treatment , the mean ( + /-SE ) area under the curve ( AUC ) during the oral glucose tolerance test of insulin ( AUC(insulin ) ) decreased significantly more in the metformin group , compared with the placebo group [ -3574 + /- 962 vs. + 1367 + /- 1021 micro IU/min.ml ( -26 + /- 7 vs. + 10 + /- 7 nmol/min.liter ) , P = 0.003 ] , but the AUC of DCI-IPG ( AUC(DCI-IPG ) ) decreased similarly in both groups ( -1452 + /- 968 vs. -2207 + /- 1021%/min , P = 0.60 ) . However , the ratio of AUC(DCI-IPG)/AUC(insulin ) increased by 160 % after metformin and decreased by 29 % after placebo ( P = 0.002 between groups ) . Moreover , metformin seemed to improve the positive correlation between AUC(DCI-IPG ) and AUC(insulin ) but not placebo ( r = 0.32 , P = 0.68 at baseline ; r = 0.52 , P = 0.12 after metformin ; and r = -0.39 , P = 0.30 after placebo ) . We conclude that in obese women with PCOS , metformin may improve the action of insulin in part by improving insulin-mediated release of DCI-IPG mediators , as evidence d by increased bioactive DCI-IPG released per unit of insulin BACKGROUND Obese women with polycystic ovary syndrome ( PCOS ) manifest impaired insulin-stimulated release of a d-chiro-inositol-containing inositolphosphoglycan ( DCI-IPG ) insulin mediator during oral glucose tolerance testing ( OGTT ) , which appears to be restored by the administration of metformin . This suggests that either obesity or PCOS is associated with a defect in the coupling of the stimulation of the insulin receptor by insulin to the release of the DCI-IPG mediator . The objective of this study was to compare the release of bioactive DCI-IPG between normal nonobese women and obese PCOS women during stimulation with two different concentrations of insulin when glucose levels are clamped . METHODS We performed a cross-sectional case-control study at the clinical research center of an academic medical center . A two-step euglycemic-hyperinsulinemic clamp was carried out in 8 nonobese normal and 8 obese PCOS women , during which DCI-IPG bioactivity was monitored . RESULTS At baseline , PCOS women were significantly more obese , hyperinsulinemic , and insulin resistant than the controls . During the clamp studies , DCI-IPG bioactivity increased significantly over the first 45 min of the low-insulin step of the clamp in normal nonobese women ( P = 0.046 ) and then decreased to baseline levels ; DCI-IPG increased again after initiation of the high-insulin step ( P = 0.029 ) . Despite higher insulin levels during the clamp in PCOS women , DCI-IPG bioactivity remained flat throughout both insulin steps and was thus significantly lower than in controls during the initial periods of both steps . CONCLUSIONS The coupling between insulin action and the release of the DCI-IPG mediator is selectively impaired in obese PCOS women , which may contribute to the insulin resistance in these women
BACKGROUND The pathogenesis of polycystic ovary syndrome ( PCOS ) has been linked to the development of insulin resistance and hyperinsulinemia .
The objective of this study is to investigate the effects of insulin sensitising agents such as D-chiro-inositol ( DCI ) on ovulation and insulin resistance in women with PCOS .