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In the present study insulin (I) and GH secretion was studied in a group of twenty-five young adolescent girls (mean age: 15±0.23 yr) with cycle irregularity associated to clinical signs of hyperandrogenism in comparison with that observed in eleven normal matched subjects with regular menses. All patients underwent basal hormone measurements and, on two consecutive days, an oral glucose tolerance test (OGTT) and a GHRH iv test. Therefore, all subjects had a transabdominal US scan for the measurement of ovarian volume and the characterization of ovarian morphology. On the basis of the US examination we found patients with poly-cystic ovaries (PCO-like group) and subjects with multifollicular ovaries (MFO group). PCO-like group exhibited T (p<0.01) and LH (p<0.05) plasma levels higher than control group and the highest free androgen index (FAI) values (13±0.87). All patients with irregular menses showed plasma concentrations of AUC for I (AUC-I) significantly higher in respect to control group (7359.4±709 vs 5447±431 μIU/ml × 180min, p<0.01) as well as both PCO-like group and MFO group did (p<0.001 and p<0.01) respectively. MFO group showed higher values of the AUC for GH (AUC-GH) (2809±432 ng/ml × 120min) in respect to controls (1708±208 ng/ml × 120min, p<0.05) and PCO-like subjects (p<0.001), who on the contrary showed the lowest AUC-GH values (618±119 ng/ml × 120min). In conclusion, PCO-like patients associated hyperinsulinemia with a blunted GH secretion while MFO patients had higher GH secretion associated with higher AUC-I values in a way suggesting an immature and still developing reproductive system.

The aim of this study was to evaluate the impact of a three-month continuous administration of oral E2, alone, or combined with 2 different dosages of dydrogesterone, on the glucose tolerance and insulin sensitivity in postmenopausal women. In a prospective placebocontrolled study, 43 normal weight and normoinsulinemic women were randomized to receive either 2 mg of oral 17β?E2 daily (group A), or 2 mg E2 daily plus 5 mg daily oral dydrogesterone, from day 14 to 28, in a sequentially combined regimen (group B), or 2 mg of E2 and 10 mg dydrogesterone in the same sequentially combined regimen (group C) or placebo for 12 weeks. An OGTT and a euglycemic hyperinsulinemic clamp were performed before and after treatment. Serum glucose and insulin concentrations were measured both in fasting conditions and after OGTT. C-peptide pancreatic secretion was tested only in fasting conditions. Total body glucose utilization (M), for insulin sensitivity evaluation, was determined in each subject. Postmenopausal women treated with unopposed 17β E2 (group A) showed a slight but statistically significant decrease of insulin sensitivity (p<0.05). A more marked deterioration of the same parameter was observed in the 2 groups treated with E2 plus dydrogesterone (group B and group C: p<0.01). Post hoctesting for the percent change from baseline indicated that group A significantly differed from group C (p<0.05) and all treated groups significantly differed from the placebo group (p<0.01). Finally, after treatment in group C, a significant reduction of insulin and an increase of glucose responses to OGTT (p<0.01) were observed. These results indicate that, in a short-term period, the use of 17β?E2 and overall 17β?E2 plus dydrogesterone, even with the reduction of insulin plasma levels, might cause a decrease in insulin sensitivity in normal weight and normoinsulinemic post-menopausal women.

Laparoscopic myomectomy is still a debated procedure and there are conflicting opinions regarding the recurrence rate. Laparoscopic myomectomy may present a higher risk of recurrence compared with abdominal myomectomy. The aim of this investigation was to analyse the recurrence rate of myomas after surgery. From January 1991 to June 1998, 165 myomectomies were performed for symptomatic myomas measuring at least 3 cm in diameter and numbering seven or less per patient. During the first 3 years of this survey, 81 patients were randomized for abdominal or laparoscopic myomectomy. Transvaginal ultrasound examination was performed within 15-30 days of surgery and every 6 months for a post-operative period of 40 months. The two groups had similar pre-operative clinical features and the number and volume of myomas did not differ between the two groups. At the end of the study the group of abdominal myomectomies showed nine recurrences (23%) against 11 (27%) of the laparoscopic group. In order to evaluate the recurrence rate in relation to several risk factors, laparoscopic myomectomies were performed from 1991 in 84 patients who agreed to follow-up (and were not in the randomized group). Of these, 78 patients were evaluated with transvaginal ultrasound for a mean interval of 26 months and 17 (21.78%) recurrences were found. Most recurrences (75%) were seen at ultrasound between 10 and 30 months after surgery. The patient's age, pre- and post-operative gravidity and parity had no influence on recurrence. Neither the number of myomas removed nor the depth of penetration or size were positively associated with the risk of recurrence. However, an associated risk factor was pre-operative gonadotrophin-releasing hormone agonist treatment (P < 0.02). None of the women with recurrence required additional surgery. We conclude that laparoscopic myomectomy is a reliable procedure. The recurrence rate is similar to that seen after abdominal myomectomy.

OBJECTIVE: To evaluate the impact on glucose and insulin metabolism of transdermal estrogen patches before and after the addition of cyclic dydrogesterone in postmenopausal women. DESIGN: We studied 21 postmenopausal women seeking treatment for symptomatic menopause. All patients received transdermal 50 micrograms/day estradiol for 24 weeks. After 12 weeks of treatment, 10 mg/day dydrogesterone were added. METHODS: During both regimens, insulin and C-peptide plasma concentrations were evaluated after an oral glucose tolerance test (OGTT); insulin sensitivity was evaluated by a hyperinsulinemic euglycemic clamp technique. Insulin and C-peptide response to OGTT were expressed as area under the curve (AUC) and as incremental AUC; insulin sensitivity was expressed as mg/kg body weight. Fractional hepatic insulin extraction (FHIE) was estimated by the difference between the incremental AUC of the C-peptide and insulin divided by the incremental AUC of the C-peptide. Plasma hormone and lipid concentrations were assessed at baseline and at 12 and 24 weeks of treatment. RESULTS: Nine patients proved to be hyperinsulinemic and 12 were normoinsulinemic. Transdermal estrogen treatment significantly decreased the insulin AUC (P < 0.05) and the insulin incremental AUC in hyperinsulinemic patients; addition of dydrogesterone further decreased both the AUC and incremental AUC of insulin. Estrogen alone and combined with dydrogesterone evoked a significant increase in C-peptide AUC in hyperinsulinemic (79.2%) and normoinsulinemic (113%) patients. The treatment increased the values for FHIE and insulin sensitivity in all patients (P < 0.04) and in the hyperinsulinemic group (P < 0.01), whereas it did not affect such parameters in normoinsulinemic patients. CONCLUSIONS: Transdermal estrogen substitution alone and combined with cyclical dydrogesterone may ameliorate hyperinsulinemia in a selected population of postmenopausal women.

Uncertainties regarding the pathogenetic changes underlying the polycystic ovarian syndrome (PCOS) have been reported. The aim of this study was to investigate the endocrine and metabolic features of PCOS patients in relation to luteinizing hormone (LH) secretion. Androgen assays, oral glucose tolerance tests, hyperinsulinaemic euglycaemic clamps and gonadotrophin releasing hormone (GnRH) tests were performed in 100 patients. Sixty-six patients scheduled as hyperinsulinaemic and 34 as normoinsulinaemic showed similar concentrations of LH, follicle stimulating hormone (FSH), LH/FSH ratio, and LH response to GnRH testing. Hyperinsulinaemic subjects showed higher body mass index (BMI), insulin resistance, testosterone and free androgen index levels compared with those of normoinsulinaemic subjects; when clustered in relation to their LH basal concentrations, the two groups obtained differed only in androstenedione concentrations. Considering both insulin and LH plasma concentrations, four groups were obtained. Hyperinsulinaemia and hyper-LH secretion were not related in 54% and coexisted in the same subjects in 26% of cases. Hyperinsulinaemia as well as hyper-LH secretion affected the expression of the syndrome; the insulinaemia was directly correlated with testosterone concentrations and all metabolic parameters that affected the free androgen index. The LH concentrations were related to androgen production and were independent of BMI and insulin concentrations. It is concluded that the degree of hormonal alteration is the final sum of such pathogenetic factors.

In a previous study, we showed an imbalance in the cytotoxic phenotype of circulating PBMC of IBD patients, possibly related to an alteration in the cytotoxic activity, which might play a role in the immunopathogenesis of IBD. γ/δ T cells, which are increased in the PBMC of IBD patients, represent a minor population of peripheral lymphocytes displaying cytolytic potential and showing both MHC and non-MHC cytotoxicity. This study was performed in order to verify their role in the cytotoxic activity of PBMC from IBD patients and correlate this activity to UC and CD, respectively. We observed a decreased NK cytotoxicity of PBMC in both UC and CD patients and this findings was unrelated to γ/δ T lymphocytes. In fact, both total and γ/δ-depleted PBMC of IBD patients, showed comparable lytic activity. On the contrary, the ADCC lytic activity was within normal range in our patients, ad was not modified by removal of γ/δ cells. The increase of Vδ1+ T cells, previously observed in our patients, seems to be unrelated to this functional impairment, because of a low cytotoxic activity displayed by this subset. Alternatively, the expanded Vδ1+ T cells could be involved in the pathogenesis of the autoimmune phenomena observed in IBD, by a mechanism different from cytotoxicity, such as autoantibodies production and/or loss of tolerance.

In order to test the hypothesis that endogenous opiates are at least partially responsible for hyperinsulinaemia in patients with polycystic ovarian disease (PCOD), the effect of naloxone (an opiate receptor blocker) on the insulin response to oral glucose load (OGTT) was studied in 20 women with PCOD and 17 control subjects at days 5-8 of their follicular phase. After fasting overnight for 10-12 h, each woman received an i.v. bolus injection (2 mg) of naloxone or an equal volume of saline infusion followed by a constant infusion of naloxone or saline solution at a rate of 8 ml/h (1 mg/h of naloxone) for 5 h. OGTT (75 g) was performed 1 h after the bolus injection. The naloxone study was performed 48 h after the saline study. Naloxone did not modify the insulin response to OGTT in either group. When the data were related to the insulin response, in PCOD hyperinsulinaemic patients, naloxone significantly reduced (P less than 0.02) the insulin response to OGTT without any change in glycaemic response curves. In control and PCOD normoinsulinaemic patients, naloxone did not change significantly either the glycaemia or the insulin levels after OGTT. No change of gonadotrophin and steroid secretion was found in any patient receiving naloxone. In conclusion, endogenous opiates may play a significant role in hyperinsulinaemia in PCOD.

In order to evaluate the acute insulin response after i.v. injection of glucagon in polycystic ovary syndrome (PCOS), 35 women affected by PCOS and 11 normo-ovulatory controls underwent a 75 g oral glucose tolerance test (OGTT) and, 2 days later, a glucagon test (1 mg i.v.). Patients were analysed according to their degree of obesity; the insulin release after glucagon injection for lean PCOS subjects and control women was not statistically significantly different. Conversely obese PCOS patients had higher insulin secretion after both i.v. glucagon and OGTT when compared to the other groups. Moreover the insulin secretory patterns were heterogeneously represented in lean and obese PCOS women. When the patients were analysed according to their insulinaemic response to OGTT, normoinsulinaemic PCOS women and control subjects had a similar insulin response to i.v. glucagon whereas the hyperinsulinaemic PCOS group had a higher insulin response (P < 0.0001). Moreover, a highly significant relationship was found between the insulin response to OGTT and to glucagon administration in the PCOS population (P < 0.0001; r = 0.73), which was maintained also after controlling for obesity. Our results are consistent with the hypothesis that PCOS patients could have an insulin hyper-response to glucagon administration, that is partially independent from obesity and related to their insulinaemic status. Moreover, the glucagon test could represent an effective alternative to OGTT in screening insulin disorders of PCOS patients (at least in the absence of other risk factors), due to its reliability, simplicity, and speed of performance.

Aim of our study is to assess the effect of a long-term oral opiate antagonist treatment during the luteal phase on the hypothalamic-pituitary-ovarian axis. Fourteen normovulatory women partecipated to the study. Immediately after the ovulation, the patients were randomly divided in two groups: in the first one women received naltrexone 50 mg/die orally (Antaxone Zambon Italy) from day 1 of the luteal phase for 7 days. In the second patients were treated with placebo for the same period and served as control group. On day 7, patients were hospitalized for a pulse pattern study followed by a GnRH test. LH, FSH, Estradiol, Progesterone were assayed. The naltrexone administration strongly increased the number as well as the amplitude of the gonadotropin pulses. The circulating P levels were also significantly higher in treated patients. The GnRH injection significantly increases the gonadotropin secretion in all patients. The stimulated LH and FSH secretion was significantly greater in treated patients when compared to controls. Such discharge of LH determined a significant increase of progesterone production in controls, but failed to stimulate the corpus luteum in treated patients. In conclusion the present paper strengtheen an important role of the opioidergic system in the regulation of GnRH pulsatility in luteal phase. Moreover, our findings confirms the sensibility of the corpus luteum to LH and the possibility to stimulate the P secretion during the luteal phase.

The relationship between insulinaemia and obesity and glucose tolerance and the impact of pregnancy as risk factor for carbohydrate abnormalities were investigated in 91 consecutive patients with polycystic ovary syndrome (PCOS) aged 26-32 years. Fifteen normoglycaemic patients became pregnant within 6 months of the pregestational study using pharmacological induction of ovulation. Plasma concentrations of insulin and glucose after an oral glucose tolerance test (OGTT) were determined by immunoradiometric assay and glucose oxidase technique respectively. OGTT patients were classified according to their response as normoinsulinaemic (n = 46) or hyperinsulinaemic (n = 45). Impairment of glucose metabolism occurred in 12.1% (n = 11, 10 obese and one lean) of all PCOS subjects. Based on insulin secretion, 6.5% of normoinsulinaemic and 13.3% of hyperinsulinaemic patients had an impaired glucose tolerance and 2.3 and 2.2% respectively a non-insulin-dependent diabetes mellitus. Obese patients had higher values for area under the curve for insulin response to OGTT (I-AUC values) than lean patients, and the percentage above ideal body weight was greater in hyperinsulinaemic than in normoinsulinaemic patients. All hyperinsulinaemic (7/15) subjects who became pregnant developed an impairment of glucose metabolism during pregnancy. It is concluded that the PCOS population was at higher risk of developing carbohydrate abnormalities than the normal population of a similar reproductive age. Furthermore, those with abnormal insulin secretion at the pregestational stage may, during pregnancy, develop an impaired gestational glucose tolerance or gestational diabetes.

A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide:insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.

Serum levels of CA-125, CA-15-3 and TAG-72 were measured in 81 patients with endometriosis, diagnosed by laparoscopy, and staged according to the Revised American Fertility Society, and in 31 control subjects.The values of CA-125 and CA-15-3 were also determined in peritoneal fluid. The aim of the present study was to evaluate the clinical usefulness of these various markers in the diagnosis of endometriosis by using them either by themselves or combined. High serum levels of CA-125 were found in 43 of 81 patients with endometriosis (53%) and in five of 38 control subjects (13%). The values of serum CA-125 progressively increased in relation to the severity of the disease. High serum values of CA-15-3 and TAG-72 were also found in patients with endometriosis, but with a similar incidence also in control patients. High CA-125 and CA-15-3 values in peritoneal fluid were found in all patients investigated.These results suggest that measurement of serum CA-15-3 and TAG-72 in addition to CA-125, does not provide any advantage for the diagnosis of endometriosis.

The aim of this study was to evaluate the impact of reduced peripheral insulin sensitivity, beta cell hypersecretion and reduced hepatic insulin clearance in the hyper-insulinaemia of lean and obese PCOS patients. A total of 35 women with polycystic ovary syndrome (PCOS) and 10 lean normo-ovulatory controls underwent an oral glucose tolerance test and an euglycaemic-hyper-insulinaemic clamp study. PCOS patients were classified into four groups according to their BMI and insulin secretion (normo-lean; normo-obese; hyper-lean; hyper-obese), and results were compared between groups and with the controls. All the PCOS groups showed significantly higher insulin secretion than controls; there were no differences in insulin response to glucose load between lean and obese normo- and hyper-insulinaemic patients. Secretion of c-peptide was greater in PCOS groups than controls. All the hyper-insulinaemic PCOS patients had lower values of hepatic insulin clearance, independent of BMI, when compared either with controls (P < 0.001) or with PCOS normo-insulinaemic women (P < 0.01). Normo- and hyper-insulinaemic obese patients had similar total body glucose utilization (M value), which was lower than in lean PCOS subjects and controls. Our results suggest that evaluation of insulin resistance alone does not fully characterize the PCOS population; differences in liver metabolism of insulin are present in obese insulin resistant subjects and in lean patients with normal insulin sensitivity when divided into normo- and hyper-insulinaemic subgroups. Insulin resistance and hyper-insulinaemia may represent two distinct features of the insulin disorder in PCOS: the former appear to reflect the presence of obesity, while the latter may be a primary feature of PCOS.

A total of 17 women affected by polycystic ovarian disease (PCOD) were studied to evaluate the involvement of endogenous opioids in the pathophysiology of the hyperinsulinism in PCOD by administering naltrexone, an oral opioid antagonist. An oral glucose tolerance test (OGTT) was performed at baseline (on day 5 of the cycle) and repeated after 6 weeks of naltrexone administration. Plasma glucose, insulin and connecting peptide (c-peptide) concentrations were evaluated in all samples. Based on their insulinaemic response to OGTT, patients were classified as hyperinsulinaemic or normoinsulinaemic. Naltrexone treatment significantly (P < 0.007) reduced the insulin response to OGTT in the hyperinsulinaemic group without affecting the c-peptide incremental area; in the normoinsulinaemic group there was a slight, but not significant, increase in both c-peptide and insulin incremental areas. The two groups showed similar c-peptide incremental areas after naltrexone treatment. There was no significant difference in the c-peptide: insulin incremental areas molar ratio between the two groups; after treatment, a significant increase in this ratio was observed in both groups. When we considered the data as an expression of the fractional hepatic extraction of insulin, we found a lower value for hyperinsulinaemic in comparison with normoinsulinaemic patients (not significant), and a significant (P < 0.01) improvement of this parameter in the hyperinsulinaemic group after naltrexone administration. In conclusion, we suggest that the contribution to hyperinsulinaemia in PCOD patients may be at least in part due to both increased pancreatic secretion and reduced hepatic removal of insulin. Chronic pharmacological inhibition of opioid tone could improve the insulin plasma concentration by acting chiefly on the liver metabolism of insulin in hyperinsulinaemic patients.

The relationship between insulinaemia and obesity and glucose tolerance and the impact of pregnancy as risk factor for carbohydrate abnormalities were investigated in 91 consecutive patients with polycystic ovary syndrome (PCOS) aged 26–32 years. Fifteen normoglycaemic patients became pregnant within 6 months of the pregestational study using pharmacological induction of ovulation. Plasma concentrations of insulin and glucose after an oral glucose tolerance test (OGTT) were determined by immunoradiometric assay and glucose oxidase technique respectively. OGTT patients were classified according to their response as normoinsulinaemic (n = 46) or hyperinsulinaemic (n = 45). Impairment of glucose metabolism occurred in 12.1% (n = 11, 10 obese and one lean) of all PCOS subjects. Based on insulin secretion, 6.5% of normoinsulinaemic and 133% of hyperinsulinaemic patients had an impaired glucose tolerance and 23 and 2.2% respectively a noninsulin-dependent diabetes mellitus. Obese patients had higher values for area under the curve for insulin response to OGTT (I-AUC values) than lean patients, and the percentage above ideal body weight was greater in hyperinsulinaemic than in normoinsulinaemic patients. All hyperinsulinaemic (7/15) subjects who became pregnant developed an impairment of glucose metabolism during pregnancy. It is concluded that the PCOS population was at higher risk of developing carbohydrate abnormalities than the normal population of a similar reproductive age. Furthermore, those with abnormal insulin secretion at the pregestational stage may, during pregnancy, develop an impaired gestational glucose tolerance or gestational diabetes.