1 Department of Microbiological and Gynaecological Sciences, University of Catania, and 2 Department of Obstetrics and Gynaecology, University of Siena, Siena, Italy
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Abstract |
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Key words: hyperinsulinaemia/insulin/PCOS/sandostatin
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Introduction |
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An increased ovarian cytochrome P450c17 activity is reported in obese women with PCOS (Ehrmann et al., 1992
; White et al., 1995
), and P450c17
appears to be stimulated by insulin in PCOS. Furthermore, a reduced insulin release linked to weight loss (Jakubowicz and Nestler, 1997
) is able to decrease ovarian P450c17
activity and serum-free testosterone concentrations in obese women with PCOS. Even if obesity is a common feature in many PCOS patients, not all women with PCOS are obese and/or hyperinsulinaemic (Chang et al., 1989
; Dale et al., 1992a
), and in non-obese patients with hyperinsulinaemia the pathogenesis of the disorder may differ from that in obese women.
Many non-obese women with PCOS exhibit an intrinsic form of insulin resistance that is unique to the disorder (Dunaif et al., 1987, 1989
), increased ovarian P450c17
activity (Barnes and Rosenfeld, 1989; Ehrmann et al., 1992
), and are hyperinsulinaemic when compared with controls (Morales et al., 1996
).
There are agents available that decrease insulin secretion, e.g. metformin (Nagi and Yudkin, 1993; Velazquez et al., 1994
), diazoxide (Nestler et al., 1989
) and somatostatin (Prelevic et al., 1990a
; Fulghesu et al., 1995
). The biguanide, metformin, does improve insulin sensitivity, but its major action is to reduce gluconeogenesis, resulting in decreased hepatic glucose production (De Fronzo et al., 1991
; Nagi and Yudkin, 1993
). Metformin administration has resulted in decreased insulin and androgen concentrations in PCOS women (Ehrmann et al., 1997
; Morin-Papunen et al., 1998
), but this could be the result of weight loss, because its insulin-sensitizing effects seem to be mediated mainly by weight reduction (Bates and Whitworth, 1982
; Kiddy et al., 1992
). Diazoxide treatment is able to reduce both insulin and androgen concentrations in obese PCOS patients by decreasing the release of insulin (Nestler et al., 1989
).
Somatostatin inhibits insulin and LH secretion in healthy adults, and octreotide, a long-acting somatostatin analogue, significantly reduces insulin, integrated LH, LH pulse amplitude and androgen concentrations in hyperinsulinaemic PCOS patients (Prelevic et al., 1990b; Fulghesu et al., 1995
).
Consequently, these findings might have implications for the treatment of hyperinsulinaemic PCOS patients. However, a significant decompensation in glucose tolerance has been reported during metformin and octreotide therapy in hyperinsulinaemic overweight (Prelevic et al., 1990a) and hyperinsulinaemic obese (Fulghesu et al., 1995
) PCOS patients respectively.
The majority of studies carried out were carried out on overweight or obese PCOS patients with hyperinsulinaemia, and few data are available concerning the effects of these agents in lean hyperinsulinaemic PCOS patients (Nestler and Jacubowicz, 1997) or in normo-insulinaemic PCOS patients. Since it has recently been reported that fasting serum glucose and the area under the serum glucose curve do not change during metformin therapy in lean hyperinsulinaemic PCOS women despite the decrease in the insulin response (Nestler and Jacubowicz, 1997) it is postulated that, similarly, short-term therapy with octreotide might induce a reduction of insulin concentrations without modifying the glucose profile in non-obese PCOS patients with hyperinsulinism.
In this way, octreotide could be suitable for the treatment of hyperandrogenism and hyperinsulinism in these patients. Furthermore, because octreotide also reduces both LH pulse amplitude and integrated LH concentrations in PCOS patients (Prelevic et al., 1990b; Fulghesu et al., 1995
), and might induce, indirectly, a decrease in the ovarian androgen production by reduction of LH stimulation, the insulin and androgen profiles were evaluated after octreotide therapy in a group of lean normoinsulinaemic PCOS patients.
The aims of the study were: (i) to evaluate whether octreotide was able to decrease insulin release and androgen concentrations in lean PCOS patients with hyperinsulinaemia, such as reported in obese or overweight PCOS subjects with hyperinsulinaemia (Prelevic et al., 1990a; Fulghesu et al., 1995
); (ii) to amplify the findings concerning the octreotide-related gonadotrophins and androgen serum modifications and their correlation with insulin values in PCOS patients. Octreotide therapy was, therefore, carried out in lean normoinsulinaemic PCOS patients and in lean PCOS patients with hyperinsulinaemia; and (iii) to investigate whether the reduction of octreotide-related insulin release may induce a decompensation of glycaemic response in lean hyperinsulinaemic PCOS subjects.
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Materials and methods |
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All the women were aged 1829 years, were in good health, and none had taken any medication known to affect carbohydrate metabolism or gonadal function for at least 6 months before the study. Spontaneous onsets of puberty and normal sexual development were reported in both patients and control subjects. Since puberty, all patients had been affected by hirsutism and oligoamenorrhoea, whereas the control subjects showed no abnormal growth and/or body distributions of hair but had regular menses.
In all subjects, a clinical examination and an evaluation of hirsutism score by the FerrimanGallwey Classification (Ferriman and Gallwey, 1961) were performed for each woman, a BMI (determined as weight in kg/height in m), and a body fat distribution (determined on the basis of the waist/hip ratio, WHR) were evaluated (Table I
).
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All subjects had an OGTT, receiving a 75 g glucose load at 07:00 after eating a standard diet (300 g carbohydrate) for 3 days and fasting overnight for 1012 h. Blood was sampled through an in-dwelling i.v. catheter at 0, 30, 60, 90, 120, 150, 180 and 240 min after glucose ingestion.
The patients underwent 7 days of treatment with a long-acting somatostatin analogue, octreotide (100 µg s.c. twice per day; Serono, Rome, Italy). At the end of treatment, the same endocrine evaluation and OGTT were repeated in all patients.
Procedures and assays
After overnight fasting, one blood sample was taken from each patient through an in-dwelling catheter placed in the antecubital vein. The blood sample was centrifuged 6000 r.p.m. x 10 min, and the sera from all samples were pooled and stored at 20°C until determination of fasting glucose, insulin, total testosterone, androstenedione, 17-OHP, DHEA-S, oestradiol, SHBG, PRL and cortisol had been performed. The last blood sampling was followed by administration of a standard oral glucose load (75 g Dextro O.G T. Saft; Boehringer Mannheim, Mannheim, Germany). Blood was sampled through an indwelling i.v. catheter at 0, 30, 60, 90, 120, 150, and 180 min after the glucose ingestion. The blood samples were centrifuged and sera were stored for determination of insulin. Plasma glucose values were determined by the glucose oxidase method (Bathelmai and Czok, 1962). Insulin concentrations were determined by a commercially available radioimmunoassay kit (Technogenetics, Milan, Italy), the intra- and inter-assay coefficients of variation for the insulin assay were 5.0 and 8.0% respectively.
A normal glycaemic response to the OGTT was defined according to the criteria of the National Diabetes Data Group (Kahn et al., 1976) (normal glucose tolerance: plasma glucose mg/ml; 0 min <115, peak value <200, 120 min <140, impaired glucose tolerance: 115140 mg/dl plasma glucose; >200, 140199; diabetes mellitus: >140, >200, >200 respectively. A normal insulinaemic response to OGTT was considered as a maximum insulinaemic concentration of 100 µg IU/ml, as established by the standard procedure of our laboratory. This threshold value was obtained from our control population of 58 lean non-hirsute young women with eumenorrhoea studied during the early follicular phase. LH, FSH, total testosterone, androstenedione and DHEA-S were measured using commercially available kits for double-antibody radioimmunoassay methods (Technogenetics). Measurement of plasma 17-OHP was performed by double-antibody radioimmunoassay methods (Pantex, Santa Monica, CA, USA) and SHBG (Interech, Strasen, Luxenbourg). Cortisol concentrations were measured using commercial kits (Diagnostic Products, Los Angeles, CA, USA). All samples were assayed in duplicate. The intra-assay coefficients of variation of LH and FSH were 4.8 and 6.8% respectively, and the inter-assay coefficients of variation were 10.5 and 10.2% respectively. The intra- and inter-assay coefficients of variation for each steroid were as follows: 8.2 and 10.5% for total testosterone; 8.8 and 11.2% for androstenedione; and 5.7 and 9.9% for DHEA-S respectively. The intra- and inter-assay coefficients of variation for 17-OHP were 5.0 and 5.4%; and for SHBG, 5.0 and 5.6% respectively. The intra- and inter-assay coefficients of variation for oestradiol, cortisol and PRL were 4.8, 9.2 and 6.4% respectively. All results were expressed as means ± SD. Normal limits of serum androgen and SHBG refer to results obtained from a group of 58 lean and healthy young women. These values were 1.7 ng/ml for androstenedione (conversion factor to SI units 0.0349); 0.8 ng/ml for total testosterone (conversion factor to SI units 0.0347); 3.0 µg/ml for DHEA-S (conversion factor to SI units 0.002714); 0.8 ng/ml for 17-OHP (conversion factor to SI units 0.03026) and 1.53.5 nmol/ml for SHBG (conversion factor to SI units, 0.002613). Ovarian volume was calculated by ultrasound vaginal examination during the follicular phase in all subjects according to the formula 4/3 [pi]x(d1/2xd2/2xd3/2), in which the diameters (d) were determined as the mean of the length, width, and depth of the ovary.
Statistical analysis
Data are expressed as mean ± SD. Individual changes from baseline pre-treatment values were analysed using the paired t-test or by the Wilcoxon signed rank test.
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Results |
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Figures 1 and 2 show the glycaemic and insulinaemic responses to OGTT (expressed as curves) in PCOS patients and controls. All women (patients and controls) showed normal fasting glycaemic and insulinaemic concentrations. The glycaemic response to the OGTT was normal in all women, showing a regular glucose tolerance (Figure 1
).
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Regarding insulinaemic response after OGTT, the PCOS patients were classified as `normoinsulinaemic' (group A, n =7) or as `hyperinsulinaemic' (group B, n = 9) with respect to the theshold value obtained in 58 healthy young women previously studied.
Changes in clinical and endocrine parameters and in glycaemic and insulinaemic response with octreotide. There were no significant changes in BMI, WHR or blood pressure during drug treatment in all patients. No relevant modifications of basal LH, FSH, total testosterone, androstenedione, 17-OHP, DHEA-S, oestradiol, SHBG, PRL and cortisol serum concentrations were observed in normoinsulinaemic PCOS patients (group A) after 7 days of octreotide administration (Table II). On the contrary, a significant decrease in the serum concentrations of LH (12.2 ± 1.9 versus 19.6 ± 2.0, P < 0.01), total testosterone (0.9 ± 0.3 versus 1.1 ± 0.4, P < 0.05) and androstenedione (1.9 ± 0.8 versus 2.8 ± 0.8, P < 0.05), and a significant increase of SHBG serum concentrations (38.6 ± 5.6 versus 25.3 ± 6.3, P < 0.05) were observed in hyperinsulinaemic PCOS patients (group B) after 7 days of octreotide administration with respect to the pretreatment values.
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On the contrary, in hyperinsulinaemic patients (group B), a significant decompensation of glycaemic response to OGTT was observed with respect to the values observed in the pretreatment period (glucose concentrations before and after octreotide treatment): 30 min: 128 ± 16 versus 152 ± 10, P < 0.05; 60 min: 132 ± 12 versus 175 ±12, P < 0.01; 90 min: 119 ± 12 versus 146 ± 14 mg/dl, P < 0.05 (Figure 4).
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Discussion |
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The decrease in insulin release due to weight loss (Jakubowicz and Nestler, 1997) or linked to metformin treatment (a biguanide whose major action is decreasing gluconeogenesis and, thus, reducing hepatic glucose production (De Fronzo et al., 1991
; Nagi and Yudkin, 1993
) decreases ovarian P450c17
activity and serum free testosterone concentrations in obese PCOS women.
Although insulin resistance is a nearly universal finding in obese PCOS subjects (Chang et al., 1983; Dunaif et al., 1989), insulin resistance in PCOS does not appear to be dependent on obesity (Chang et al., 1989
; Dale et al., 1992a
), even though it appears to be amplified by obesity. There is less unanimity about the presence of insulin resistance in non-obese PCOS patients (Chang et al., 1989
; Dunaif et al., 1989
; Dale et al., 1992b
), and studies in lean PCOS patients have reported conflicting results. However, many non-obese women with PCOS demonstrate an intrinsic form of insulin resistance, which is unique to the disorder (Dunaif et al., 1987
, 1989
), and are hyperinsulinaemic compared with their healthy counterparts (Morales et al., 1996
). These non-obese PCOS patients with hyperinsulinaemia also exhibit an increased ovarian P450c17
activity (Dunaif et al., 1989
; Ehrmann et al., 1992
), and Nestler et al. have recently demonstrated that hyperinsulinaemia stimulates ovarian P450c17
activity in lean women with PCOS (Nestler and Jakubowicz, 1997
). Moreover, these authors have reported that by decreasing serum insulin with metformin in the lean PCOS subjects it is possible to obtain a reduction of ovarian cytochrome P450c17
activity and, thus, to improve the hyperandrogenism (Dunaif et al., 1989
). Because metformin treatment decreases the serum insulin response to OGTT in normal women, but does not affect serum androgens in the same subjects, it has been postulated that the observed decrease in serum androgens in lean PCOS patients treated with metformin was not due to the drug itself, but was secondary to the reduction of insulin release (Dunaif et al., 1989
).
There are several agents available that decrease circulating-insulin values by improving insulin sensitivity and/or by reducing pancreatic insulin release or enteral glucose absorption. Such agents could be used in insulin-resistant hyperandrogenic women because they may improve both associated endocrine and metabolic parameters. As previously reported, metformin treatment significantly reduces insulin and androgen serum concentrations in both obese and non-obese PCOS patients (Velazquez et al., 1994; Morin-Papunen et al., 1998
). Diaxozide, an
-adrenergic drug, is similarly able to reduce insulin and testosterone concentrations in obese PCOS patients (Nestler et al., 1989
). Acarbose, a synthetic disaccharide that reversibly prevents the presence of
-glucosidase in the brush-border of the intestinal mucosa, decreases disaccharide digestion and, consequently, reduces enteral monosaccharide absorption (Toeller, 1991
). In hyperinsulinaemic pre-menopausal women with hypertestosteronaemia it was shown that a decline of ovarian androgens was achieved in association with a flattening of the post-prandial glucose and insulin increase by long-term treatment with acarbose (Geisthovel et al., 1996
). Another class of insulin-sensitizing agents, the thiazolidinediones, produce marked improvements in muscle insulin sensitivity (Iwamoto et al., 1991
; Hoffmann and Colca, 1992
; Nolan et al., 1994
), and one of these agents, troglitazone, improves total body action, resulting in lower insulin, LH, androstenedione, free testosterone, oestradiol, and oestrone serum concentrations, and in higher SHBG concentrations, in obese PCOS women (Dunaif et al., 1996
).
In PCOS patients, octreotide alters ovarian sensitivity to gonadotrophin stimulation as measured by the FSH threshold, because it lowers ovarian sensitivity to FSH through suppression of insulin-like growth factor-I (IGF-I)/IGF binding protein-3 (IGFBP-3) (Van der Meer et al., 1998).
A previous study showed that octreotide induces significant decreases in LH pulse amplitude and in LH response to buserelin (Prelevic et al., 1990), and suggested that a causal relation exists between the pattern of LH secretion and insulin concentration in PCOS patients (Prelevic et al., 1990b). The findings are consistent with in-vitro data which show a positive correlation between LH production with insulin concentrations in pituitary cell cultures (Adashi et al., 1981
). Although octreotide seems to act directly at the pituitary level, probably by decreasing the sensitivity of gonadotrophins to gonadotrophin-releasing hormone (GnRH), the analogue could also influence LH indirectly by lowering insulin values, which in turn decreases the sensitivity of the gonadotrophins. In this way, Fulghesu et al. had previously demonstrated a connection between the excessive secretion of insulin and LH in a specific group of PCOS patients (Fulghesu et al., 1995
).
It appears that octreotide has not previously been administered to a selected group of lean hyperinsulinaemic PCOS patients to reduce insulin release. Since it has recently been reported that fasting serum glucose and the area under the serum glucose curve do not change during metformin therapy in lean PCOS women despite the decrease in the insulin response (Nestler and Jakubowicz, 1997), it is postulated that, similarly, in lean PCOS patients with hyperinsulinaemia, treatment with octreotide could induce a reduction of insulin values without modifying the glucose profile in the same patients.
On the other hand, because it has been shown that octreotide reduces both LH pulse amplitudes and integrated LH concentrations in PCOS patients, and consequently could induce a decrease of the ovarian androgen production by decreasing LH-stimulation, in this study the effects of octreotide, per se, on the gonadotrophin secretion in normoinsulinaemic PCOS patients were evaluated.
This study confirms that in a subgroup of PCOS patients hyperinsulinaemia is independent of weight or obesity, because our patients had a regular BMI and were hyperinsulinaemic. In our patients, octreotide was able to significantly reduce insulin secretion only in hyperinsulinaemic PCOS women, whereas no modifications of insulin secretion were observed in normoinsulinaemic patients. The observed reduction of androgen concentrations during octreotide therapy in hyperinsulinaemic patients only confirms that the decrease of serum insulin with the drug reduces the hyperandrogenism in these patients, as was demonstrated with metformin in other lean PCOS hyperinsulinaemic patients (Nestler and Jakubowicz, 1997), probably reducing ovarian cytochrome P450c17
activity, which is abnormally stimulated by hyperinsulinaemia (Jakubowicz and Nestler, 1997
). This effect seems to be limited to ovarian C19 steroids since DHEA-S, the adrenal androgen marker, was not affected, as has been previously shown.
It is not possible to exclude the presence of a direct pituitary action of octreotide on LH secretion, when serum concentrations are decreased with respect to the pretreatment values after therapy. In this way, the observed reduction of serum androgen concentrations in the hyperinsulinaemic group could be determined also, or only, by a decrease in the LH-dependent androgen ovarian production.
On the other hand, octreotide could have altered the ovarian sensitivity to LH stimulation, lowering ovarian responsiveness to LH stimulus and, in turn, decreasing LH-dependent ovarian androgen production, e.g. on ovarian sensitivity for FSH in PCOS patients treated with octreotide and FSH in a low dose step-up protocol (Van der Meer, 1998).
Moreover, the absence of any modification of LH serum concentrations in the group of normoinsulinaemic patients after octreotide therapy seems to exclude a direct pituitary effect of octreotide on gonadotrophin secretion, and strongly suggests that the reduction of androgen concentrations observed in hyperinsulinaemic patients is linked to the decrease in insulin concentrations.
The reported positive correlation between LH and insulin concentrations only in the hyperinsulinaemic group of patients, but not in patients with normoinsulinaemia, suggests that there is an increased sensitivity or responsiveness of gonadotrophins to GnRH stimulation, probably linked to insulin concentrations. Furthermore, insulin seems to increase pituitary responsiveness and sensitivity in both obese (Prelevic et al., 1990) and lean (Nestler and Jakubowicz, 1997) PCOS patients. The decompensation of glycaemic response after OGTT observed in this study after normalization of insulin response linked to octreotide therapy is unclear. Several studies on the mechanism of insulin insensitivity in classic insulin target tissue in PCOS patients have reported a decreased insulin sensitivity and responsiveness without any changes in insulin binding in adipocytes (Dunaif et al., 1992
). It can be postulated that in a subgroup of lean PCOS patients with hyperinsulinaemia, the increased response of insulin to glucose may represent a compensatory mechanism for the maintenance of normal glycaemic homeostasis. It is possible that an extrinsic factor to the insulin receptor may cause this abnormality, as previously postulated (Dunaif et al., 1996
). The administration of a drug, e.g. octreotide, that decreases insulin release, without increasing insulin sensitivity in the target-tissue, could induce a decompensation of glucose homeostasis because it reduces the compensatory increase of insulin release for the maintenance of regular glycaemic concentrations in these subjects. Due to the absence in our patients of concomitant factors (such as overweight or obesity) that could, per se, determine a reduced insulin sensitivity in the target-tissue and, consequently, a secondary, compensatory increase in insulin concentrations, it is suggested that in this group of PCOS patients the augmented insulin secretion represents an effective compensatory mechanism for the maintenance of glucose homeostasis, probably linked to post-binding receptor abnormalities as previously proposed (Ciaraldi et al., 1992
). Hyperinsulinaemia, in turn, stimulates ovarian P450c17
activity and determines hyperandrogenism.
In conclusion, this study has shown that in lean hyperinsulinaemic PCOS patients the administration of octreotide, which only improves insulin secretion without modifying insulin sensitivity in the target tissue, does not appear suitable for the treatment of hyperinsulinaemic PCOS patients, because even if octreotide is able to normalize insulin and, indirectly, androgen secretion, it also induces a decompensation in glycaemic homeostasis, which could in turn determine several metabolic abnormalities during long-term treatment in these patients. On the contrary, a pharmacological treatment with drugs which reduce enteral glucose absorption, e.g. acarbose, or which decrease hepatic glucose production, such as metformin, or which produce marked improvements in muscle insulin sensitivity, e.g. troglitazone, could represent an appropriate alternative treatment for the management of hyperinsulinaemic PCOS patients.
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Acknowledgments |
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Notes |
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References |
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Submitted on March 29, 1999; accepted on September 21, 1999.