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Objective: Treatment with metformin, an insulin-lowering agent, increases serum glycodelin, a progesterone-regulated lipocalin protein of the reproductive axis that may play a role in foeto-maternal defence mechanisms. This finding led to the hypothesis that insulin might decrease serum glycodelin concentration., Design, Patients and Measurements: Euglycaemic hyperinsulinaemic clamp experiments (n = 50) were carried out on 28 women of reproductive age (range 25-47 years; mean +/- SEM 39 +/- 1.0 years), and the results were analysed with respect to their baseline serum progesterone (< 10 or > or = 10 nmol/l) and glycodelin (< 10 or > or = 10 microg/l, equivalent to < 357 or > or = 357 pmol/l) concentrations at the onset of the clamp. Ten clamp experiments were performed on five women wearing a levonorgestrel-releasing intrauterine device (IUD), and these were analysed as a separate group., Results: Contrary to the hypothesis, no acute glycodelin-lowering effect of insulin was found in any of the groups studied. All the small rises in glycodelin levels detected during acute hyperinsulinaemia occurred in the comparisons of medians and not means, and all such changes took place within the limits seen in the women with no progesterone exposure. In the group with low progesterone/low glycodelin (n = 21), glycodelin showed a small but significant increase at 30 and 90 min of the clamp (P < 0.01). In the group with elevated progesterone/low glycodelin (n = 11), there was a slight glycodelin increase at 30 min (P < 0.05), whereas no increase was found in the group with elevated glycodelin levels (n = 8). In the clamp experiments on women with levonorgestrel-releasing IUD, the basal glycodelin level was low in all cases and, as in the other women with low glycodelin levels, glycodelin was slightly increased at 30, 60 and 90 min of hyperinsulinaemia (P < 0.01)., Conclusions: The results rule out any acute glycodelin-reducing effects of insulin, although indirect long-term effects mediated by insulin on glycodelin secretion cannot be excluded.

Production of insulin-like growth factor-binding protein-1 (IGFBP-1) by the liver is efficiently inhibited by insulin both in vivo and in vitro. Consequently, serum IGFBP-1 concentration reflects insulin bioactivity in portal vein. Sex hormone-binding globulin (SHBG) is another insulin-regulated liver-derived protein that has appeared promising in detecting individuals with portal hyperinsulinemia. We compared the regulation of IGFBP-1 and SHBG production by insulin and insulin-like growth factors (IGF-I and IGF-II) in human hepatoma cell cultures. Insulin equipotently inhibited IGFBP-1 and SHBG production, with maximal decrease in culture medium concentrations being about 35% for both proteins during 48 h of culture in serum-free medium. IGF-I and IGF-II also inhibited the IGFBP-1 and SHBG levels. We conclude that IGFBP-1 and SHBG are equally sensitive to ambient insulin concentrations in human hepatoma cell cultures, and the production of both proteins is also attenuated by the IGFs.

We hypothesized that hyperinsulinemia contributes to early pregnancy loss in the polycystic ovary syndrome by adversely affecting endometrial function and environment. Serum glycodelin, a putative biomarker of endometrial function, is decreased in women with early pregnancy loss. Insulin-like growth factor-binding protein-1 may also play an important role in pregnancy by facilitating adhesion processes at the feto-maternal interface. We studied 48 women with polycystic ovary syndrome before and after 4 weeks of administration of 500 mg metformin (n = 26) or placebo (n = 22) 3 times daily. Oral glucose tolerance tests were performed, and serum glycodelin and insulin-like growth factor-binding protein-1 were measured during the follicular and clomiphene-induced luteal phases of menses. In the metformin group, the mean (+/-SE) area under the serum insulin curve after glucose administration decreased from 62 +/- 6 to 19 +/- 2 nmol/L.min (P < 0.001). Follicular phase serum glycodelin concentrations increased 20-fold from 150 +/- 46 to 2813 +/- 1192 pmol/L (P < 0.001), and serum insulin-like-growth factor-binding protein-1 concentrations increased from 936 +/- 152 to 2396 +/- 300 pmol/L (P < 0.001). Similarly, luteal phase serum glycodelin concentrations increased 3-fold from 3434 +/- 1299 to 10624 +/- 1803 pmol/L (P < 0.001), and serum insulin-like growth factor-binding protein-1 concentrations increased from 1220 +/- 136 to 4916 +/- 596 pmol/L (P < 0.001). Uterine vascular penetration also increased in the metformin group, as did blood flow of spiral arteries, as demonstrated by a 20% decrease in the resistance index from 0.71 +/- 0.02 to 0.57 +/- 0.03 (P < 0.001). These variables did not change in the placebo group. We conclude that insulin reduction with metformin increases follicular and luteal phase serum glycodelin and insulin-like growth factor-binding protein-1 concentrations and enhances luteal phase uterine vascularity and blood flow in the polycystic ovary syndrome. These changes may reflect an improved endometrial milieu for the establishment and maintenance of pregnancy.

Objective: To examine the effects of the synthetic somatostatin-analogue octreotide and human recombinant insulin on the release of insulin-like growth factor binding protein-1 (IGFBP-1) and P from human granulosa-luteal cells., Design: Primary culture of human granulosa-luteal cells., Setting: Academic research laboratory., Patient(s): Women undergoing oocyte retrieval for IVF-ET because of tubal infertility., Intervention(s): Octreotide or insulin were added to the cultures; sampling of culture medium was performed after 48 hours., Main Outcome Measure(s): Insulin-like growth factor binding protein-1 and P., Result(s): Octreotide significantly inhibited IGFBP-1 (58.8% compared with controls) and P release (66.1% compared with controls). Insulin abolished IGFBP-1 release while stimulating P release (200.7% compared with controls). There was a significant and positive correlation between IGFBP-1 and P levels., Conclusion(s): Octreotide and insulin have a significant effect on human granulosa-luteal cell function in terms of IGFBP-1 and P release. Our results suggest a local ovarian mechanism for the recently observed effects of octreotide in the treatment of women with polycystic ovary syndrome.

The pathophysiological mechanism underlying polycystic ovarian disease (PCOD) is different in obese and lean women. In obese patients the basic disorder is insulin resistance and hyperinsulinemia. In non-obese women the dominant derangement is a relative excess of luteinizing hormone (LH) and growth hormone (GH) production. The levels of GH, LH, sex hormone binding globulin (SHBG) and insulin-like growth factor binding protein-1 (IGFBP-1) were significantly lower and insulin levels considerably higher in obese PCOD women as compared to their non-obese counterparts. There was, however, no difference in the mean IGF-1 levels found in these two groups. The present study was designed to investigate whether, in addition to the mean levels, the overnight pattern of GH, IGF-1, IGFBP-1 and SHBG differed in obese women with polycystic ovaries as compared to that observed in the non-obese PCOD patients. Eight women with PCOD diagnosed by clinical, sonographic and hormonal means were studied. Four had basal body mass index exceeding 27. Blood samples were collected every 20 min over a period of 8 h, starting at 23:00 h. Twenty-four samples were collected from each patient and examined in one batch for GH, IGF-1, IGFBP-1, SHBG and insulin. The secretion patterns of the above substances during the late night (23:00-03:00 h) and early morning (03:00-07:00 h) hours were examined and compared in obese and non-obese PCOD women. Neither GH nor IGF-1 showed a distinct overnight secretion pattern. The overnight secretion patterns of IGFBP-1 and SHBG were similar in obese and non-obese women--the former showing a constant rising during the night and the latter exhibiting a converse trend. The integrated insulin levels were much higher during the late night as compared to early morning hours in all patients. It is proposed that the specific secretion pattern of IGFBP-1 is not directly dependent on body fat mass but is regulated by insulin in both obese and non-obese patients.

The short and long term effects of GH on serum concentrations of insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin were investigated in women participating in an in vitro fertilization program. In this placebo-controlled study, sterile saline (eight women) or 24 IU GH (eight women) were given im on alternate days, starting on cycle day 4, in combination with GnRH and human menopausal gonadotropin. IGFBP-1 levels decreased significantly during the first 4 h after GH administration, whereas no significant changes were seen in the placebo group. The concentrations of serum IGF-I and insulin did not change during 4 h after GH injection. During the 11-day follow-up period, serum levels of both IGF-I and insulin were significantly higher in GH-treated than in placebo-treated women. These results suggest that the serum concentration of IGFBP-1 is not completely GH independent. They also support the earlier findings that long term treatment with GH increases serum IGF-I and insulin levels.

Dietary factors are known to modulate concentrations of sex hormone-binding globulin (SHBG). In the present study we have investigated the possibility that insulin like growth factor-type I (IGF-I) may be an additional regulator of SHBG using cultured human hepatoma cells which secrete SHBG. The inhibitory effect of insulin on SHBG secretion by these cells was confirmed but, in addition, IGF-I was shown to inhibit SHBG secretion by about 40% at a concentration of 100 nmol/l. A similar degree of inhibition was achieved using insulin at a concentration of 10 mumol/l. Insulin, but not IGF-I, was also found to inhibit the secretion of a low molecular weight IGF-binding protein (IBP-I), which is also secreted by hepatoma cells. It is concluded that IGF-I is an additional regulator of SHBG secretion by these cells and that it may be involved in regulating SHBG secretion in vivo in response to dietary factors.

We previously demonstrated that supraphysiological insulin concentrations reduced the plasma 34K insulin-like growth factor-binding protein (IGF-BP) concentrations in humans. In this study we examined whether physiological changes in plasma insulin concentrations regulate IGF-BP and, if so, whether the regulation is influenced by race, glucose tolerance, or rate of glucose metabolism. For these purposes we 1) analyzed the relationship between fasting plasma insulin and IGF-BP concentrations in 2 racial groups (23 caucasians and 35 southwestern American Indians), 2) measured the response of plasma IGF-BP to oral glucose in 20 normal subjects, and 3) determined the dose-response characteristics of plasma IGF-BP to glucose and insulin in 23 normal subjects at 4 different insulin and glucose concentrations. The fasting plasma insulin concentration was inversely related to the plasma IGF-BP concentration in both the caucasian and Indian groups (P less than 0.0001). In the caucasian group the mean plasma IGF-BP concentration was higher [15 +/- 4 (+/- SE) micrograms/L] than in the Indian group (8 +/- 2 micrograms/L; P less than 0.05). This difference was independent of race and glucose tolerance, and it could be explained by lower plasma insulin concentrations in the caucasian (387 +/- 50 pmol/L) than in the Indian group (215 +/- 43 pmol/L; P less than 0.001). After oral glucose administration, the insulin concentration (423 +/- 72 pmol/L) was maximal 30 min after glucose treatment, and significant suppression of the IGF-BP concentration occurred at 90 min. Analysis of the dose-response curves revealed maximal suppression of IGF-BP at about 1150 pmol/L insulin, and half-maximal suppression at about 290 pmol/L. The plasma glucose concentration or the rate of glucose metabolism had no effect on the IGF-BP concentration. These data suggest that insulin is a major regulator of plasma IGF-BP concentrations under physiological conditions.

The purpose of this study was to investigate the effect of calorie restriction on serum concentrations of sex hormone binding globulin (SHBG) in women with normal or polycystic ovaries (PCO) and to examine the possible role of insulin and insulin-like growth factor-I (IGF-I) in mediating changes in SHBG levels. Six normal subjects with mean (SD) body mass index (BMI) 25.5 (2.2) and five subjects with PCO (BMI 36.1 (3.7)) were studied before and after 2 or (PCO only) 4 weeks of a very low calorie diet (330 kcal/day; Cambridge Diet). In both normal women and patients with PCO there was a twofold increase in SHBG concentrations after 2 weeks and this was sustained in the PCO subjects for a further 2 weeks. The rise in SHBG was accompanied by a fall in free testosterone concentrations. There were parallel changes in serum insulin and IGF-I concentrations which decreased during the diet and there were significant negative correlations of SHBG with insulin in both normal subjects (r = -0.62) and women with PCO (r = -0.60). In addition, serum concentrations of an insulin-dependent small molecular weight (34 kDa) binding protein for IGF-I (IGF-BPI) increased significantly during dieting in both groups and were negatively correlated with serum insulin (controls, r = -0.56; PCO, r = -0.68) and positively correlated with serum SHBG levels (controls, r = 0.69; PCO, r = 0.63). In summary, these data indicate that in both normal subjects and those subjects with PCO, calorie restriction results in a highly significant increase in SHBG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

This study was designed to investigate the basic concentrations of different hormones in obese and non-obese patients with polycystic ovarian disease (PCOD). Eight women with PCOD, of whom four were obese with body mass index (BMI, kg/m2) of >25 and four were non-obese with BMI <25, volunteered to participate in this study. Serum samples were taken every 20 min over an 8 h period, starting at 2300 h, on day 5 of a spontaneous or gestagen-induced cycle. Basic insulin concentration was found to be significantly higher in the obese women compared with their non-obese counterparts ( < 0.0001). Serum concentrations of insulin-like growth factor binding protein (IGFBP-I) and sex hormone binding globulin (SHBG) were found to be significantly lower ( < 0.001 for both hormones) in the obese compared with the non-obese women. Serum concentrations of insulin-like growth factor I (IGF-I) did not differ between the two groups. The non-obese women had significantly higher serum concentrations of luteinizing hormone (LH) ( < 0.001) and of growth hormone (GH) ( < 0.002) than their obese counterparts. Based on these results, two models of the development of PCOD were suggested. In obese women, hyperinsulinaemia causes an excessive production of androgens through the enhancement of IGF-I receptors which, in synergism with LH, causes increased activity of cytochrome P-450c 17a. In non-obese patients, relative increase of GH concentration stimulates excessive ovarian IGF-I production. At this point synergism with LH results in excessive production of androgens by the same mechanism as in obese patients. The increase in androgen may lead to changes in important brain centres, which might cause a disturbance in gonadogrophin secretion leading to the typical changes of PCOD. [ABSTRACT FROM PUBLISHER]