Plasma Levels of Insulin-Like Growth Factor-I and Its Binding Protein in Polycystic Ovary Syndrome

Iwashita, Mitsutoshi; Mimuro, T.; Watanabe, Masao; Setoyama, Takeshi; Matsuo, A.; Adachi, Tomoko; Takeda, Yoshihiko; Sakamoto, Shinichi

doi:10.1159/000181561

Cited by 46 publications

(28 citation statements)

References 32 publications

(39 reference statements)

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“…Potential contributors to excessive growth of theca-interstitial tissues in PCOS include insulin, insulin-like growth factor 1 (IGF1), and moderate oxidative stress. Indeed, PCOS is associated with hyperinsulinemia, elevated free IGF1, and increased oxidative stress [2][3][4][5][6][7][8]. Our previous in vitro studies [9][10][11] have demonstrated that insulin, IGF1, and moderate oxidative stress (such as that induced by hypoxanthine-xanthine oxidase) stimulate proliferation of rat theca-interstitial cells.…”

Section: Introductionmentioning

confidence: 99%

Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat1

Rzepczynska¹,

Piotrowski²,

Wong³

et al. 2009

Biology of Reproduction

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Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, a rate-limiting step of the mevalonate pathway. The pleiotropic effects of statins may be due to inhibition of cholesterol synthesis, as well as decreased availability of several biologically important intermediate components of the mevalonate pathway, including two substrates for isoprenylation (farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate [GGPP]). Recently, we demonstrated statin-induced inhibition of ovarian theca-interstitial cell proliferation in vitro, as well as reduction of testosterone levels in women with polycystic ovary syndrome (PCOS). This study evaluates the relative contribution of inhibition of isoprenylation and/or cholesterol availability to the modulation of theca-interstitial proliferation. Rat theca-interstitial cells were cultured in chemically defined media with or without simvastatin, FPP, GGPP, squalene, and/or two membrane-permeable forms of cholesterol (25-hydroxycholesterol and 22-hydroxycholesterol). Simvastatin inhibited DNA synthesis and the count of viable cells. The effects of simvastatin were partly abrogated by FPP and GGPP but not by squalene or cholesterol. Inhibition of farnesyl transferase and geranylgeranyl transferase reduced cell proliferation. The present findings indicate that simvastatin inhibits proliferation of theca-interstitial cells, at least in part, by reduction of isoprenylation. These observations provide likely mechanisms explaining clinically observed improvement of ovarian hyperandrogenism in women with PCOS.

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Section: Introductionmentioning

confidence: 99%

Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat1

Rzepczynska¹,

Piotrowski²,

Wong³

et al. 2009

Biology of Reproduction

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“…Excessive growth of ovarian mesenchyme may also be due to a synergy between activin with insulin and IGF-I. Women with PCOS have typically significant hyperinsulinemia and elevated, free, bioavailable IGF-I [44][45][46][47]. In these patients, insulin and IGF-I may excessively amplify the proliferative actions of activin.…”

Section: Discussionmentioning

confidence: 99%

Activin Stimulates Proliferation of Rat Ovarian Thecal-Interstitial Cells1

Dulęba

Pehlivan

Carbone

et al. 2001

Biology of Reproduction

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There is growing evidence that the function of ovarian theca-interstitial (T-I) cells may be modulated by paracrine actions of activin, inhibin, and follistatin. Furthermore, either dysregulation, dysfunction, or both, of these peptides may play a role in conditions associated with T-I hyperplasia, such as polycystic ovary syndrome (PCOS) and hyperthecosis. This study was designed to evaluate the role of activin, inhibin, and follistatin in the modulation of T-I cell proliferation. Interaction of these peptides with insulin-like growth factor-I (IGF-I), a known stimulator of T-I cell proliferation, was also assessed. Purified rat T-I cells were cultured for 48 h in chemically defined media and with or without activin (3-30 ng/ml), inhibin (3-30 ng/ml), follistatin (100 ng/ml), and/or IGF-I (10 nM). T-I cell proliferation was assessed using radiolabeled thymidine incorporation assay. Activin alone stimulated proliferation of T-I cells in a dose-dependent fashion (by up to 320% above control; P < 0.001), whereas inhibin alone or follistatin alone had no significant effect. Inhibin had also no effect on activin-induced proliferation. Follistatin significantly reduced the stimulatory effects of activin and decreased proliferation by up to 46% (P < 0.01) below the level attained in the presence of activin alone. IGF-I (10 nM), at a dose producing a near-maximal effect, increased proliferation by 175% above control (P < 0.001); insulin (10 nM) increased proliferation by 52% above control (P < 0.03). A combination of IGF-I (10 nM) and activin (30 ng/ml) resulted in a 1090% increase of proliferation above control (P < 0.001); this stimulatory effect was significantly greater than that achieved in the presence of either activin alone or IGF-I alone (P < 0.001). Similarly, a combination of insulin (10 nM) and activin (30 ng/ml) increased proliferation by 506% above control levels. Flow cytometry evaluation revealed that activin increased the proportion of actively dividing cells (in S or G2/M phase of the cell cycle) by 42% (P < 0.02), whereas IGF-I had no effect on the proportion of actively dividing cells. The present findings indicate that an activin-follistatin system may be involved in the regulation of the size of ovarian thecal-stromal compartment. In view of the synergy between activin and IGF-I, and the difference in the effects on the cell cycle distribution, stimulation of T-I proliferation by these agents is likely to be mediated via separate transduction pathways. Excess activin or insufficient follistatin may contribute to T-I hyperplasia.

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“…The most important regulator of cir culating low-molecular-weight IGF-binding protein con centrations is insulin [12,29]. It is therefore of interest that reduced serum concentrations of a low-molecularweight IGF-binding protein have recently been demon strated in PCO [ 13,14]. IGF-I-binding protein concentra tions were significantly lower in the obese PCO patients than in those who were non-obese [13,30], and fasting serum insulin concentrations correlated negatively with the IGF-I-binding protein concentrations [ 13,31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Hyperinsulinaemia has been shown to increase ovar ian androgen production by direct stimulation of gonadal steroidogenesis and/or gonadotropin secretion [6,7], The hormone could also, as recently suggested, control the concentration of insulin-like growth factor-1 (IGF-I), which in turn may regulate ovarian function [8][9][10], Insu lin-induced alterations in IGF-1 levels could also result from direct stimulation of hepatic production [11] or from a reduction of low-molecular-weight IGF-binding protein levels [ 12], It is therefore of interest that increased IGF-I concentration was recently reported in women with PCO, in association with reduced IGF-binding protein [13,14], This supports the suggestion that PCO results from a primary abnormality in the growth hormone (GH)/IGF axis [ 15],…”

Section: Introductionmentioning

confidence: 99%

Twenty-Four-Hour Serum Growth Hormone, Insulin, C-Peptide and Blood Glucose Profiles and Serum Insulin-Like Growth Factor-l Concentrations in Women with Polycystic Ovaries

et al. 1992

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Raised insulin levels are now recognized as a characteristic feature of women with polycystic ovaries (PCO), and hyperinsulinism has been shown to stimulate androgen production in such women. We have, however, recently shown that hyperinsulinaemia is present only in the obese subjects with PCO in whom insulin concentrations correlate with those of luteinizing hormone. We therefore studied 24-hour blood profiles of growth hormone (GH) and insulinlike growth factor-I (IGF-I) in obese and non-obese women with PCO, for comparison with their levels of insulin, C-peptide and other hormones, such as androgens which are known to be disturbed in PCO. Mean 24-hour GH levels were higher overall in PCO than in control subjects, although the difference was not significant. When, however, a separate analysis was made in obese as compared with non-obese PCO patients, GH concentrations were significantly higher in the non-obese group than in the obese (p = 0.0005). There was a significant negative correlation between body mass index and mean 24-hour GH concentrations (r = -0.641; p = 0.0006). IGF-I concentrations were however similar in the PCO group overall and in controls, as well as in the obese and non-obese PCO patients. The 24-hour blood glucose profile pattern was significantly different in PCO women from controls (p = 0.009), with absence of post-prandial peaks in blood glucose concentrations. These changes were most marked in the non-obese PCO group, who also had significantly lower blood glucose levels than either controls or obese PCO subjects. Significantly higher 24-hour C-peptide and insulin concentrations were found in the obese PCO group compared with controls and the non-obese PCO group. The absence of typical post-prandial increases in insulin and C-peptide concentrations was also evident in the non-obese PCO subjects. There was a significant negative correlation between the 24-hour C-peptide and mean 24-hour GH values (r = – 0.629; p = 0.0212) in the PCO group. Our finding of higher GH concentrations in non-obese PCO patients together with lower blood glucose and normal IGF-I concentrations could theoretically be explained in terms of altered IGF-binding protein concentration, which in turn would influence the biological potency of IGF-I and regulation of GH secretion. These findings would also support the concept that part of the disturbance in patients with PCO lies between that of insulin and IGF-I binding protein.

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Plasma Levels of Insulin-Like Growth Factor-I and Its Binding Protein in Polycystic Ovary Syndrome

Cited by 46 publications

References 32 publications

Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat1

Role of Isoprenylation in Simvastatin-Induced Inhibition of Ovarian Theca-Interstitial Growth in the Rat1

Activin Stimulates Proliferation of Rat Ovarian Thecal-Interstitial Cells1

Twenty-Four-Hour Serum Growth Hormone, Insulin, C-Peptide and Blood Glucose Profiles and Serum Insulin-Like Growth Factor-l Concentrations in Women with Polycystic Ovaries

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