The effect of recombinant human growth hormone on regulation of growth hormone secretion and blood glucose in insulin-dependent diabetes.

GH hypersecretion in insulin-dependent diabetes (IDDM) is well documented. Although it has recently been shown that residual insulin secretion determines the magnitude of this GH hypersecretion, the underlying mechanisms of the disorder have not yet been clarified. The 24-h GH and blood glucose profiles, insulin-like growth factor I (IGF-I) concentrations and GH responses to GRF were analyzed in 21 insulin-dependent diabetics and 4 healthy subjects before and after 7 days treatment with recombinant human GH (rhGH) (4 IU given sc at 0800 h). According to C-peptide response to glucagon IDDM patients were subdivided into C-peptide negative (CpN, n = 12) patients without endogenous pancreatic beta-cell activity and C-peptide positive (CpP, (n = 9) patients with endogenous insulin secretion. No significant difference could be observed between the mean 24-h blood glucose profile before and after rhGH treatment in any treated group. Before and on rhGH treatment the highest 24-h GH values were observed in CpN patients when compared to CpP and controls. The rhGH treatment induced a similar increase in the mean 24-h GH concentrations in all groups studied which was statistically significant only in CpP diabetics. Mean pretreatment serum IGF-I concentrations were not significantly different between CpN, CpP patients and controls. The net increase in IGF-I concentrations after rhGH treatment was however, significantly lower in CpN patients than in CpP and control subjects. GRF-induced GH response before and after rhGH treatment was significantly greater in diabetics than in controls. The response of GH to GRF in CpN diabetics was however, almost unchanged after treatment whereas it became lower in CpP diabetics and controls. The dose of 4 IU of rhGH increased significantly GH levels in diabetics with preserved beta-cell function with consequent increase in IGF-I levels and attenuation of GRF induced GH response. In contrast, the same dose of rhGH failed to induce significant increase in GH levels in diabetics without residual beta-cell activity, most probably due to already high pretreatment levels. In addition, neither increase in IGF-I levels nor suppression of GH response to GRF on rhGH treatment was observed in CpN diabetics. The results are in keeping with an important role of portal insulin in GH-induced hepatic IGF-I secretion.

Effects of the somatostatin analogue, octreotide, in polycystic ovary syndrome.

In view of the association of hyperinsulinemia with elevated luteinizing hormone (LH) levels and hyperandrogenism in polycystic ovary syndrome (PCOS), the effect of octreotide was investigated in women with PCOS. Twelve amenorrheic women were treated with 100 micrograms octreotide twice a day for 7 days; 13 infertile women unresponsive to clomiphene citrate were treated either with octreotide (100 micrograms twice a day from day 1 of the menstrual cycle until corpus luteum formation) in addition to human menopausal gonadotropins (HMG) or with HMG alone. Octreotide significantly reduced the 4-hour integrated LH concentrations. LH pulse amplitude and nadir concentrations, and LH, testosterone, androstenedione, and estradiol responses to a gonadotropin-releasing hormone (GnRH) analogue in amenorrheic PCOS women. Octreotide treatment also resulted in a more "appropriate" hormonal milieu at the time of human chorionic gonadotropin (HCG) injection in the infertile women, with LH and testosterone levels being reduced while follicle-stimulating hormone (FSH) levels increased. Orderly follicular growth occurred, with one or two mature follicles being present at the time of HCG injection in cycles in which octreotide was given together with HMG. There were no cases of hyperstimulation, even in women who had previously hyperstimulated after HMG alone. Octreotide thus inhibits LH and androgen secretion and may improve ovulatory performance in infertile women with PCOS.

Metabolic effects of tibolone in postmenopausal women with non-insulin dependent diabetes mellitus.

OBJECTIVE: Postmenopausal women with non-insulin dependent diabetes (NIDDM) are frequently obese, hypertensive and hyperlipidaemic and hence at particular risk of coronary heart disease (CHD). They might therefore benefit from menopausal therapy. In view of the improvement in insulin sensitivity and the reduction in triglyceride levels induced by tibolone in healthy postmenopausal women we evaluated the effects of 12 months of tibolone on glycaemic control, serum insulin and lipid levels in postmenopausal women with NIDDM. DESIGN: A prospective 12 months before/after intervention study. PATIENTS: Fourteen postmenopausal women (mean age 58.14 +/- 1.25 years; mean duration of menopause 121.21 +/- 13.42 months; mean BMI: 26.55 +/- 0.97) with NIDDM (mean duration of diabetes 113.79 +/- 13.89 months). MEASUREMENTS: Fasting and postprandial blood glucose levels were assessed monthly, serum fructosamine, fasting and postprandial insulin every 3 months and serum lipids (total cholesterol, triglyceride, HDL-cholesterol and LDL-cholesterol) every 6 months. RESULTS: Changes in blood glucose, both fasting and postprandial, were not statistically significant during the treatment period. Serum fructosamine concentration increased significantly after 9 months. A significant decrease in fasting and postprandial insulin concentrations was observed after 9 months. A non-significant decrease was observed in total cholesterol, LDL cholesterol and triglyceride but no change in HDL cholesterol. Body weight did not change during the period of observation. CONCLUSION: A slight deterioration in glycaemic control, a fall in insulin concentration and no change in serum lipids were observed in women with NIDDM during 12 months treatment with tibolone.

Effect of recombinant human growth hormone treatment on insulin-like growth factor (IGF-I) levels in insulin-dependent diabetic patients.

Basal and recombinant human growth hormone (rhGH)-stimulated insulin-like growth factor (IGF-I) levels were studied in 19 insulin-dependent diabetic patients and 4 healthy subjects. Diabetic patients were divided according to glucagon test result into CpN (10 patients without residual beta cell activity) and CpP (9 patients with preserved beta-cell activity) and CpP (9 patients with preserved beta-cell activity) groups, and according to age into three groups (A = 21-30 years; B = 31-40 years; C = 41-50 years). All control subjects belonged to group B. Blood glucose and growth hormone were measured at hourly intervals and IGF-I every 6 h during 24 h before and after 7 days treatment with 4 IU of rhGH given subcutaneously at 8 p.m. The age-related decrease in basal IGF-I levels was evident in both CpN and CpP groups of diabetic patients. IGF-I net increase with rhGH treatment was variable and insignificant in comparison with basal value without age-related differences in CpN diabetics. Progressively larger, age-related increases in IGF-I concentrations were observed in CpP diabetic patients. This study indicates impairment of hepatic IGF-I generation capacity in diabetic patients without residual beta-cell activity and the importance of simultaneous actions of portal insulin and GH on hepatic IGF-I production.

The effect of somatostatin analog octreotide (Sandostatin) on luteinizing hormone and ovarian steroids in insulin-dependent diabetic women without residual insulin secretion.

In order to determine whether the inhibitory effect of octreotide on luteinizing hormone (LH) secretion and ovarian steroids observed in women with polycystic ovaries (PCO) is a direct or indirect action of the analog, we have investigated the effect of 7 days of octreotide on LH, follicle stimulating hormone (FSH) and ovarian steroids in nine insulin-dependent diabetic women without residual insulin secreting, as in these patients a possibly confusing inhibitory effect of octreotide on endogenous insulin production is excluded. LH and FSH pulsatility over 4 h and hormonal responses (LH, FSH, estradiol, testosterone and androstenedione) to a single subcutaneous injection of buserelin were measured before and after 7 days' treatment with octreotide 100 micrograms subcutaneously twice a day. Octreotide failed to induce a significant reduction in either serum gonadotropin or ovarian steroid levels, although there was a general tendency of hormonal responses to buserelin to be lower with the analog. The effect of octreotide on LH secretion seems to be in correlation with the pretreatment levels which are, in turn, at least determined partly by endogenous insulin secretion. Thus, the results of the present study support the view that insulin has an important influence on LH secretion.

LH pulsatility and response to a single s.c. injection of buserelin in polycystic ovary syndrome.

The present study was undertaken in order to determine whether patients with polycystic ovary syndrome (PCOS) have LH pulse frequency and/or amplitude higher than those in normal cycling women during the follicular phase, and, if so, to establish possible factors which might influence LH secretion in PCOS. The study was conducted on 14 PCO patients (aged 19-30 years), who were subdivided according to the data on their cycle abnormality into 2 groups: amenorrheic (Am-PCOS, n = 9) and oligomenorrheic (O-PCOS, n = 5). LH pulsatility was assessed in the early follicular phase in controls (n = 5) and O-PCOS and at any time in Am-PCOS. Blood samples were taken every 10 minutes for 4 hours. Pulse analyses of LH data were performed using the Munro program. The buserelin test was performed on the same day by injection of 40 micrograms of buserelin (blood samples were taken every 60 minutes for the following 10 hours). Eleven PCO patients and 12 control subjects had an oral glucose tolerance test (oGTT) (blood samples were taken every 60 minutes for glucose, insulin and C-peptide measurements). Both mean LH pulse frequency and mean pulse intervals were not distinguishably different in PCO women (Am and O) and controls. In contrast, the mean pulse amplitude was significantly higher in the Am-PCOS group than in O-PCOS women and controls (p less than 0.02 and p less than 0.001, respectively). A significant positive correlation was established between nadir LH concentrations and LH pulse amplitude (r = +0.966, p less than 0.001). The LH response to buserelin stimulation was significantly higher in Am-PCOS than in O-PCOS (p less than 0.004). A highly significant positive correlation was observed between LH pulse amplitude and insulin response during oGTT (p less than 0.001) in PCO subjects. Basal (prebuserelin) LH concentrations correlated significantly with fasting insulin levels (p less than 0.008) and insulin and C-peptide responses to oGTT. These results allow us to conclude the following: 1. An increased LH pulse amplitude and an exaggerated LH response to buserelin observed in amenorrheic PCO subjects compared to those in oligomenorrheic PCO subjects fail to support the hypothesis of an intrinsic hypothalamo-pituitary abnormality. 2. The relationship between fasting and glucose-stimulated insulin levels with LH nadir concentrations, pulse amplitude and response to buserelin suggests an etiological role of insulin in the pathogenesis of PCOS.

Changes in prolactin levels with the menopause: the effects of estrogen/androgen and calcitonin treatment.

Prolactin levels were evaluated over a 2-year period in three groups of postmenopausal women: group A consisted of 35 untreated women distributed according to time since the menopause; group B consisted of 17 women on a combined estrogen/androgen preparation (Gynodian depot) intramuscularly at monthly intervals; and group C consisted of 12 women on 100 units of salmon calcitonin intranasally on alternate days and 1500 mg calcium daily. The control group (group D) consisted of 11 healthy premenopausal women. Serum prolactin, estradiol, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were measured at the onset and at 6-month intervals over 24 months. Mean serum prolactin concentrations decreased significantly during the second postmenopausal year in untreated women p = 0.0001 and p = 0.0000 after 18 and 24 months, respectively) when compared to either the levels in premenopausal women or those at the beginning of the menopause (p = 0.0007). Neither combined estrogen/androgen nor calcitonin therapy significantly influenced prolactin levels which were similar throughout the observed period. In the group on a combined estrogen/androgen preparation, physiological estradiol concentrations together with a suppression of gonadotropins during the first 6 months of therapy were achieved. In women treated with intranasal salmon calcitonin, estradiol, FSH and LH levels were unchanged. Our results show that prolactin levels decrease significantly during the second year of the menopause. Neither combined estrogen/androgen, nor salmon calcitonin therapy had any effect on serum prolactin concentrations in postmenopausal women.

24-hour serum cortisol profiles in women with polycystic ovary syndrome.

We studied the 24-h blood profiles of cortisol in obese and non-obese women with polycystic ovary syndrome (PCOS), for comparison with the levels in healthy women (controls). The levels of other hormones, such as androgens, which are known to be disturbed in PCOS, were also compared. Luteinizing hormone (LH) and androgen (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)) concentrations were significantly (p < 0.005) raised in patients with PCOS, compared to those in control women. Sex hormone binding globulin (SHBG) concentration was significantly lower in women with PCOS, particularly in those who were overweight. There was a significant negative correlation between body mass index (BMI) and SHBG concentrations (r = -0.59; p = 0.006). Mean 24-h cortisol concentrations were similar in women with PCOS and controls, as well as in the obese and non-obese PCOS patients. However, the 24-h blood cortisol profile pattern was significantly different in women with PCOS as compared to the controls (p = 0.0039). Significantly lower cortisol levels were observed during the night (levels were determined between 20.00 and 04.00 and are expressed as the area under the curve) in subjects with PCOS, compared to the control women (p = 0.02). These changes were most marked in the non-obese women with PCOS who had lower blood cortisol levels during the night than either the controls or the obese PCOS subjects. Our finding of significantly lower cortisol concentrations during the night could reflect a subtle abnormality of adrenal steroid secretion in women with PCOS.

Effects of a low-dose estrogen-antiandrogen combination (Diane-35) on clinical signs of androgenization, hormone profile and ovarian size in patients with polycystic ovary syndrome.

This study evaluates the effect of an oral contraceptive containing 35 micrograms of ethinyl estradiol and 2 mg of cyproterone acetate (Diane-35) on hormone dynamics, clinical signs of androgenization and ovarian size in patients with polycystic ovary syndrome (PCOS). Forty-six patients with PCOS were treated with Diane-35 for between 9 and 30 cycles without interruption (a total of 688 cycles). Clinical and hormonal evaluations were performed before treatment and every 3rd cycle during the treatment period while ultrasonographic assessment of ovaries was carried out every 6th cycle. A highly significant decrease in the LH/FSH ratio (p less than 0.001) as well as testosterone levels (p less than 0.001) was noticed after the 3rd cycle of Diane-35 administration. The mean serum androstenedione level decreased significantly (p less than 0.025) after the 3rd cycle, and showed a lowering trend thereafter. A significant reduction in serum DHEA-S levels was observed after the 6th cycle of treatment and they also showed a subsequent lowering trend. A highly significant increase in SHBG concentrations (p less than 0.001) was noticed after the 3rd cycle. Most of the patients noticed improvement in hirsutism between the 8th and 12th cycles of treatment. Mean ovarian size decreased significantly (p less than 0.001) after the 6th cycle, the normal size being reached after the 12th cycle of treatment. After the 4th cycle treatment was discontinued in 1 patient due to secondary amenorrhea, and in another 3 patients because of an increase in diastolic blood pressure. In a few patients side-effects such as weight gain, breast tenderness and mood changes in mild form were reported. Three out of 7 patients conceived in the 2nd or 3rd cycle after discontinuing Diane-35 therapy. The results of this study show that a combination of low-dose estrogen and cyproterone acetate (Diane-35) successfully reduces the hormonal disturbances which characterize PCOS. Apart from the normalization of the hormonal profile and the decrease in ovarian size, beneficial effects of Diane-35 were also observed on acne, hirsutism and regulation of the menstrual cycle. Favourable effects were also seen in terms of the pregnancy rate after discontinuation of Diane-35 therapy.