Proyecto de Mejoramiento Vial de Colinas Del Norte (PROMEVAC)

Insulin mU/L ■ Control □ PCOS

IGFBPl

0 T — '— 1— '— I— '— I— '— I— "— I— '— I— '— I— '— I— '— I— '— I— '— I— r

There were significant negative correlations between the 24hr median concentration of insulin and both SHBG (p<0.05) and IGFBPl (p<0.01). The correlation between SHBG and total testosterone was not significant (r=-0.49). There was no correlation between IGF-1 and insulin, IGFBPl or SHBG. The subjects in the two groups had similar body mass indices and so these correlations are independent of weight.

4.3.4.

DISCUSSION

The absence of a diurnal variation of SHBG in the two groups of women has been reported in a small group of four women (Yie et al. 1990) but there are no previous studies comparing hyperandrogénie women with weight matched controls. A small diurnal variation in males that is thought to be related to the early morning increase in testosterone levels has been reported (Clair et al. 1985, Plymate et al. 1989). The small decrease in men is thought to reflect an increased clearance of SHBG mediated by testosterone rather than a decrease in hepatic SHBG synthesis. This concept is supported by evidence that sex hormones alter the glycan microheterogeneity pattern of SHBG and thence its rate of clearance (Tardivel-Lacombe and Degrelle 1991). The significant difference in SHBG levels between the two groups, which was independent of their testosterone concentrations and their BMI, in association with a significant negative correlation with insulin reported in this study provides additional evidence to support insulin as a more potent inhibitor of hepatic SHBG production than testosterone in women. The inhibition of SHBG produc­ tion by insulin occurs in the presence of a sustained overall increase in insulin concentra­ tions and is not apparently altered acutely by the daily variation in insulin concentrations.

The diurnal changes in IGFBPl are similar to those reported by Suikkari et al. (1988). The close correlation of these changes to variations in insulin concentrations provides evidence for a regulatory role of insulin on IGFBPl levels. The alteration in concentrations is very rapid and the rate of decrease is similar in the two groups despite widely differing insulin levels. It has been suggested that these rapid changes in IGFBPl concentrations allow an

Clinical Studies increased concentration of "free" IGF-1 and that this may be an important mechanism in the maintainance of glucose homeostasis (Lewitt and Baxter 1990). The difference in the 24 hour median secretion of IGFBPl and insulin between the two groups is to be expected since women with anovulatoiy PCOS have previously been reported to have lower IGFBPl concentrations (Suikkari et al. 1989a) and raised fasting insulin concentrations (Dunaif et al. 1988, Shaip 1991) compared to weight matched controls. The rapid decline in IGFBPl concentrations to changes in insulin is in contrast to that of SHBG and is similar to the responses of the two binding proteins to an oral glucose tolerance test (Section 4.2.3.). This probably reflects the difference in the half-life of the two binding proteins which is approximately 30 minutes for IGFBPl and 5-7 days for SHBG (Julkenen et al. 1988, Anderson et al. 1976). It was therefore predicted that SHBG would not exhibit any diurnal variation.

Insulin concentrations varied during the 24 hours in both groups although a statistically significant diurnal variation in secretion could only be detected in the control group. The lack of diurnal variation in the women with PCOS demonstrated in this study implies that regardless of the carbohydrate load women with PCOS secrete excess insulin throughout the day. The fact that the two groups did not receive the same glucose load during the 24 hours is a valid criticism of this study. However the finding that the difference in the peak concentrations remains significant after the four hours following the oral GTT have been excluded indicates that these differences in insulin secretion are evidence of true hyperinsulinaemia and not secondary to variations in glucose load. Furthermore, evidence exists that equivalent calorie loads, regardless of carbohydrate content, induce similar insulin responses (Peterson and Jovanovic-Peterson 1991). The finding that the insulin concentrations started rising in the PCOS group prior to the administration of the glucose provides additional evidence of hyperinsulinaemia and probable insulin resistance in women with PCOS (Dunaif et al. 1988,1989, Sharp et al. 1991).

The lack of variation in IGF-1 concentrations is consistent with other studies of diurnal variation (Holly et al. 1988). Changes in IGF-1 levels have been reported following fasting

(Clemmons et al.l982, Kiddy et al. 1989) and exercise (Suikkari et al. 1989b). The similarity in the levels of IGF-1 is interesting and the absence of any correlation with insulin, SHBG and IGFBPl is in contrast to the findings of other studies (Conway 1990) when IGF-1 was found to be positively correlated with insulin and IGFBPl.

The increased insulin concentrations in the women with PCOS support the concept that these women are at greater risk of developing non-insulin dependent diabetes (Dunaif and Graf 1988). All the women in the PCOS group were anovulatory and there is evidence that hyperinsulinaemia only occurs in this group and that ovulatory women with PCOS are neither hyperinsulinaemic nor insulin resistant (Sharp et al. 1991, Robinson et al. 1993). In vitro evidence in cultured ovarian stromal cells has demonstrated that insulin increases the production of testosterone (Barbieri 1986). In granulosa cells from normal and polycystic ovaries, insulin and IGF-1 increase FSH stimulated oestradiol production (Erikson et al. 1990) and decrease IGFBP-1 production (Mason et al. 1993). It is not known whether the ovary is insulin resistant in women with polycystic ovary syndrome but it is possible that hyperinsulinaemia may play a role in the mechanism of anovulation in these women.

In summary these data indicate that there is no diurnal variation in SHBG concentrations in women. The previously reported diurnal variation in IGFBPl and the close relationship between insulin and IGFBPl is confirmed. The median concentration of SHBG correlated more strongly with insulin than testosterone or BMI implying that the persistently raised insulin concentrations found in obese and annovulatory PCOS women acts as a principal inhibitor of SHBG concentrations. This finding explains the increased incidence of significant hirsutism in thin anovulatory and obese women with PCOS as a decrease in SHBG concentrations leads to an increase in free ("biologically active") testosterone concentrations. This study does not provide evidence for the coregulation of hepatic SHBG and IGFBPl production by insulin. The increased insulin concentrations and the lack of diurnal variation in women with PCOS confirms the tendency to insulin resistance in these women which is independent of obesity and suggests that hyperinsulinaemia is sustained over a 24 hour period.