Polycystic ovarian syndrome: a follow-up study on fertility and menstrual pattern in 149 patients 15-25 years after ovarian wedge resection.

BACKGROUND: The aim of this study was to evaluate fertility and menstrual pattern in women with polycystic ovarian syndrome (PCOS) 15-25 years after ovarian wedge resection (OWR). METHODS AND RESULTS: The diagnosis was based on the combination of ovarian pathology and symptoms. The 149 patients, all primarily treated at a university teaching hospital, were studied three times by means of a questionnaire up to 25 years after surgery. Kaplan-Meier analysis showed a cumulative rate of spontaneous pregnancies of 76%, increasing to 88% when induced pregnancies were included. The cumulated live birth rate was 78%. A bootstrap simulation indicated that 69.5% would develop post-operative adhesions, which could impede pregnancy in 13.4%. In the majority of the patients a regular menstrual pattern was restored up to 25 years after OWR. CONCLUSION: The results of OWR in PCOS are favourable to most modern treatments. Laparoscopic electrocautery of the ovaries is the only method equally successful, and, by being less invasive, it has made OWR history in the treatment of PCOS.

A preliminary study of circadian serum cortisol concentrations in response to a 72-hour fast in rheumatoid arthritis patients not previously treated with corticosteroids.

The aim of the study was to investigate the effects a 72-h fast upon serum total and free cortisol concentrations in RA patients not previously treated with glucocorticoids. Total serum cortisol and transcortin concentrations were measured in four RA patients with active disease at 4-h intervals during two 24-h periods (1200 h-1200 h), the first while eating a normal diet (fed state) and the second during the last 24 h of a 72-h water fast. Free cortisol concentrations were calculated from the total cortisol and transcortin values. The 3-day fast increased overall 24-h free and total cortisol concentrations by 50% and 35%, respectively. This was due largely to a marked increase in nocturnal serum cortisol concentrations during fasting, particularly at 0400 h, when mean total and free cortisol levels were increased by 170% and 260% compared to the fed state. Between 2000 and 0800 h overall total- and free cortisol concentrations were increased by 72% and 99%, respectively. These results suggest that an increase in nocturnal concentrations of cortisol occurs in response to fasting in RA patients not previously treated with glucocorticoids. These increases may mediate the beneficial clinical response previously found in studies of longer fasting periods in RA patients.

Serum levels of interleukin-6 and dehydroepiandrosterone sulphate in response to either fasting or a ketogenic diet in rheumatoid arthritis patients.

OBJECTIVE: To investigate the effects of either a 7-day fast or a 7-day ketogenic diet upon serum interleukin-6 (IL-6) and dehydroepiandrosterone sulphate (DHEAS) in RA patients. METHODS: We measured serum concentrations of DHEAS and IL-6 in 23 RA patients with active disease, 10 of whom followed a 7-day sub-total fast and 13 of whom consumed a ketogenic diet (isoenergetic, carbohydrate < 40 g/day) for 7 days. Clinical and laboratory variables were measured at baseline, on day 7 and after re-feeding on day 21. Correlation analyses were used to assess the associations between serum IL-6, DHEAS and disease activity variables at each timepoint. RESULTS: Fasting, but not the ketogenic diet, decreased serum IL-6 concentrations by 37% (p < 0.03) and improved disease activity at day 7. Both fasting and the ketogenic diet increased serum DHEAS levels by 34% as compared with baseline (both p < 0.006). Levels of IL-6, but not DHEAS, correlated with several disease activity variables. CONCLUSION: Both fasting and a ketogenic diet significantly increased serum DHEAS concentrations in RA patients. Only fasting significantly decreased serum IL-6 levels and improved disease activity. As the increases in serum DHEAS were similar in response to both fasting and a ketogenic diet, it is unlikely that the fall in serum IL-6 or clinical improvements after fasting were directly related to increases in serum DHEAS. The fasting-induced fall in serum IL-6 may underlie the fall in CRP and ESR observed in RA patients in response to a 7-day fast.

Reduction in serum leptin and IGF-1 but preserved T-lymphocyte numbers and activation after a ketogenic diet in rheumatoid arthritis patients.

OBJECTIVE: To assess the clinical, immunological and hormonal effects of carbohydrate restriction in rheumatoid arthritis (RA) patients via the provision of a ketogenic diet. METHODS: Thirteen RA patients with active disease consumed a ketogenic diet for 7 days, providing the estimated requirements for energy and protein whilst restricting their carbohydrate intake to < 40 g/day. This was followed by a 2-week re-feeding period. Clinical and laboratory evaluations were carried out on days 0, 7 and 21. Changes in serum glucose, beta-hydroxybutyrate (beta-HB), leptin, insulin-like growth factor-1 (IGF-1) and cortisol were also measured at these time points. To study CD4+ and CD8+ lymphocyte responses, mitogen stimulated T-cell activation was assessed in heparinised whole blood via flow-cytometric analysis of CD69 expression. RESULTS: After the 7-day ketogenic diet, there were significant increases in serum beta-HB and cortisol, and significant decreases in body weight, the total lymphocyte count, serum leptin, IGF-1 and glucose. However, with the exception of morning stiffness, there were no significant changes in any of the clinical or laboratory measures of disease activity, or in early T-lymphocyte activation and the absolute numbers of CD4+ and CD8+ cells. CONCLUSION: In RA patients several of the metabolic and hormonal responses to a ketogenic diet, such as a fall in serum IGF-1 and leptin, resemble those which occur in response to acute starvation. However, the clinical and immunological changes which occur in response to acute starvation do not take place with a ketogenic diet and thus may be dependent upon energy and/or protein restriction.

Increased cortical bone content of insulin-like growth factors in acromegalic patients.

To investigate cortical bone composition and the role of the insulin-like growth factor (IGF) system in active acromegaly, iliac crest bone biopsies were obtained from 15 patients (3 women and 12 men), aged 21-64 yr (mean, 45.6 yr), and 25 age- and sex-matched controls (8 women and 17 men), aged 22-66 yr (mean, 44.6 yr). Levels of IGF-I, IGF-II, IGF-binding protein-3 (IGFBP-3), IGFBP-5, and total protein were determined in extracts obtained after ethylenediamine tetraacetate and guanidine hydrochloride extraction. Osteocalcin and calcium were determined in extracts after HCl hydrolysis. Cortical bone contents of IGF-I, IGF-II, and IGFBP-5 were significantly elevated in the acromegalic patients compared with control values [91% (P < 0.001), 44% (P < 0.04), and 115% (P < 0.004), respectively]. There was no significant difference in IGFBP-3, osteocalcin, protein, and calcium between patients and controls. This study suggests that the increased levels of growth factors in cortical bone from acromegalics is a reflection of local production, secondary to a chronic systemic excess of GH and IGF-I.

Biochemical markers of bone metabolism in benign human osteopetrosis: a study of two types at baseline and during stimulation with triiodothyronine.

Biochemical markers of bone remodelling were used to evaluate bone turnover in two types of autosomal dominant osteopetrosis (ADO) at baseline and during stimulation with triiodothyronine (T3). Eight patients with Type I (aged 23-61 years, mean 40.4 years) and nine patients with Type II ADO (aged 20-49 years, mean 32.8 years) were compared with 10 normal controls (aged 22-54 years, mean 35.4 years). The participants were treated with 100 microg T3 daily for 7 days and followed for a total of 16 weeks. Serum concentrations of T3 increased and corresponding suppression of TSH was observed in all participants. Both formative and resorptive bone markers were normal at baseline. After stimulation with T3, a significant increase was seen in all groups for the formative markers used. Secondary increments were observed at the end of the observation period for all groups, indicating activation of bone remodelling. A variety of resorptive markers was assessed, but no differences between patients and controls were seen. After stimulation, highly significant responses were found in all parameters in all groups, in accordance with stimulation of existing resorptive cells. However, no secondary increments were seen at the end of the observation period. A more pronounced response was found in crosslinks-related assays. The study demonstrates that it is possible to stimulate bone resorptive and formative cells with thyroid hormones in both types of ADO. Moreover, it indicates that the remodelling process is activated by a short course of T3 treatment.

An experimental study of cardiac natriuretic peptides as markers of development of congestive heart failure.

The use of cardiac peptide measurements as possible diagnostic tools in congestive heart failure has been extensively discussed in the recent literature. Therefore, the aim of this study was to establish a model of experimental chronic heart failure, and thereby perform a comparative study of secretion and circulating levels of the cardiac peptides atrial natriuretic peptide (ANP), N-terminal proatrial natriuretic peptide (N-terminal proANP) and brain natriuretic peptide (BNP) during evolving heart failure. Chronic heart failure was induced in seven pigs by rapid left atrial pacing for three weeks. The effects of failure induction were documented 24 h after pacemaker deactivation. Hemodynamic indices of cardiac preload, like pulmonary capillary wedge pressure (PCWP) and right atrial pressure (RAP), were all considerably increased compared to sham operated controls. Likewise, plasma endothelin-L, noradrenaline, renin activity, aldosterone and angiotensin II were all markedly increased. Heart failure was accompanied by significant increases in both estimated cardiac secretory rate and plasma concentrations of all three cardiac peptides, significantly correlated to the PCWP. The directional changes during evolving heart failure were similar, although the percentage increase in plasma BNP was much larger than for ANP and N-terminal proANP. In absolute molar terms, however, the BNP concentration changes were minor compared to those of the other two peptides. The larger percentage increase of BNP might indicate its superiority as a marker of heart failure development, provided a functional assay suitable for clinical use can be designed for a peptide circulating in this low concentration range.

Exercise capacity and hormonal response in adults with childhood onset growth hormone deficiency during long-term somatropin treatment.

Growth hormone (GH) deficiency in adults in associated with reduced muscular strength and peak oxygen uptake (peak Vo2). How these variables are influenced by long-term somatropin therapy in adults with childhood onset GH-deficiency has not been precisely defined. The effect of somatropin treatment in 20 childhood onset GH-deficient adults on muscular strength, maximal exercise capacity, and hormonal response to exercise were therefore examined in a double-blind placebo-controlled study with recombinant human GH (rhGH, 12 microg/kg/day) for 6 months, followed by 36 months of open-labeled uninterrupted therapy, after which treatment was stopped for 9 months. After 6 months of treatment, exercise capacity increased significantly, as assessed by time to exhaustion [mean change (95% CI) 0.8 (0.2, 1.4) min, P<0.05], total (accumulated) work [11.6 (0.8, 22.4) kJ, P<0.05] and peak Vo2 [2.6 (0.3, 4.9) ml/kg/min, P<0.01], whereas no significant changes were observed during placebo. This effect on exercise capacity remained unchanged during long-term somatropin treatment, mainly due to increased capacity among patients with isolated GH deficiency. Nine months after stopping treatment, peak Vo2 decreased by 11% from 32.8+/-2.5 to 29.1+/-2.1 ml/kg/min (P<0.05). Maximal muscular handgrip strength was not affected by treatment. Long-term GH therapy resulted in decreased respiratory exchange value (R value) at rest and during exercise (P<0.001), suggesting a metabolic role with increased fat combustion. Resting and submaximal noradrenaline levels decreased during somatropin treatment (P<0.05), while no effect was observed for other exercise-induced hormonal responses, including adrenaline, insulin, prolactin, renin, and ACTH. We conclude that somatropin therapy to childhood onset GH deficient adults has a favourable effect on exercise capacity and may have a potentially beneficial effect on plasma catecholamines.

Effect of bolus injection versus continuous infusion of furosemide on diuresis and neurohormonal activation in patients with severe congestive heart failure.

Previous studies have demonstrated that continuous infusion of furosemide results in increased diuresis and natriuresis compared with bolus administration of the drug in patients with severe heart failure. We reasoned that continuous infusion of furosemide caused less activation of neurohumoral mechanisms, since other studies have shown that bolus administration of furosemide may activate this system. We therefore tested the hypothesis that continuous administration of furosemide would increase water and sodium excretion due to less activation of neurohormones. Eight patients with severe heart failure were studied during continuous infusion over 24 h and bolus injections of furosemide twice daily in a randomized cross-over study. Bolus administration of furosemide increased diuresis and natriuresis significantly in the first 4 h after administration compared with continuous administration, but this was later reversed, resulting in similar 24 h total output. The neurohormones measured at baseline were all markedly elevated. Neither regimens of furosemide caused any further significant changes in neurohumoral response except that pro-ANF decreased more during the first 8 h after bolus administration compared to continuous infusion. This study has demonstrated that bolus administration of furosemide in conventional doses is equally effective as continuous intravenous infusion in patients with severe heart failure. This may be due to maximal neurohormonal activation in severe heart failure (NYHA III-IV) which could not be further activated by bolus administration.

Gas exchange and neurohumoral response to exercise: influence of the exercise protocol.

Maximal oxygen uptake varies with the exercise protocol, but the extent to which hormonal and metabolic responses to exercise are influenced by the exercise protocol has not been precisely defined. Twelve healthy subjects underwent maximal exercise testing using two incremental bicycle tests with individualized, identical work rate increments between 40 and 70 W. One protocol employed a 1-min and the other a 3-min duration per stage. Expiratory gas and venous blood were sampled at regular intervals for metabolic and hormonal analysis. Exercise duration for the 1-min and 3-min protocols was 6.0 +/- 0.1 and 14.3 +/- 0.3 min, respectively (P < 0.001). Significantly higher values were observed for peak VO2 and maximal ventilation during the 3-min protocol compared with the 1-min protocol (41.1 +/- 1.8 vs 38.3 +/- 1.6 ml.kg-1.min-1, P < 0.001; and 104.9 +/- 8.0 vs 97.2 + 5.7 l.min-1, P < 0.05, for peak VO2 and peak ventilation, respectively). However, the maximal workload achieved was higher during the 1-min versus the 3-min protocol (330 + 24 vs 280 + 21 W, P < 0.01). No differences were observed for maximal heart rate or blood pressure, whereas maximal plasma lactate was roughly twice as high during the 3-min compared with the 1-min protocol (7.5 +/- 0.8 vs 3.8 +/- 0.5 mmol.l-1, P < 0.001). Norepinephrine, epinephrine, dopamine, and growth hormone levels were generally higher throughout exercise during the 3-min compared with the 1-min protocol. When expressed as a percentage of peak VO2, however, differences in catecholamine levels were not observed. Endothelin levels did not change. We conclude that the exercise protocol profoundly influences exercise capacity as well as the metabolic and hormonal response to exercise and should be considered when using these variables to evaluate an intervention.

Cardiac secretion of atrial and brain natriuretic peptides in acute ischaemic heart failure in pigs: effect of angiotensin II receptor antagonism.

In a model of acute ischaemic left ventricular failure in pigs, we compared the plasma levels and cardiac secretion of the three atrial peptides, atrial natriuretic factor (ANF), N-terminal proatrial natriuretic factor (N-terminal proANF) and brain natriuretic peptide (BNP). Acute ischaemic left ventricular failure was induced by embolization of the left coronary artery with plastic microspheres. Thereafter, treatment was given by an intravenous injection of the angiotensin II receptor (AT1) antagonist losartan. Effects of failure induction and treatment were documented by measurement of haemodynamic parameters and plasma concentrations of catecholamines, plasma renin activity, angiotensin II and aldosterone. Acute left ventricular failure was accompanied by significant increases in cardiac secretion and plasma levels of all three atrial peptides, which was considerably more pronounced for ANF and N-terminal proANF than for BNP. Treatment with losartan resulted in significant decreases in plasma ANF and N-terminal proANF, whereas BNP did not change. These findings indicate that ANF and N-terminal proANF may be better suited than BNP as markers of cardiac preload during the development and treatment of acute heart failure.

Dose-dependent effects of recombinant human growth hormone on biochemical markers of bone and collagen metabolism in adult growth hormone deficiency.

Administration of growth hormone (GH) to patients with growth hormone deficiency (GHD) has beneficial effects, but so far has been employed only empirically. We have, therefore, investigated the dose-dependent effect of GH on target tissue by studying biochemical markers of bone and collagen turnover in GHD. Then patients with GHD (nine males and one female aged 21-43 years, mean age 28 years) participated in the study. Growth hormone deficiency was defined as a peak serum GH response of less than 15 mU/l in two provocation tests. After a 4-week run-in period, the study population received increasing doses of GH at 4-week intervals (1, 2 and 4 U/m2). Blood samples were collected in the fasting state at 7.00 h on the last day of each period and assayed for serum levels of osteocalcin (S-BGP), bone alkaline phosphatase (B-ALP), C-terminal propeptide of type I collagen (S-PICP), carboxy-terminal pyridinoline cross-linked telopeptide of type I collagen (S-ICTP) and N-terminal propeptide of type III collagen (S-PIIINP). Following replacement therapy, serum insulin-like growth factor I and insulin-like growth factor binding protein 3 increased sequentially with time (p < 0.001 and p < 0.001, MANOVA) and the values were elevated significantly over baseline levels after treatment with 1 U/m2. Serum BGP values were below normal at the start of the study and increased gradually following GH treatment to levels in the low-normal range. Baseline values for serum bone alkaline phosphatase (B-ALP), PICP and PIIINP were within the normal range. The collagen parameters increased with GH replacement (p < 0.001, MANOVA) to levels above normal, whereas B-ALP stayed within normal limits. Serum ICTP values were elevated above the normal range at baseline, indicating increased bone resorption in GHD. A linear increase in values was observed with GH treatment (p < 0.001, MANOVA). Serum ICTP did not correlate significantly with the bone formative parameters but was correlated positively to PIIINP. The sensitivity of S-ICTP as a bone resorptive marker is thus questioned. In conclusion, a dose-dependent increase in markers of growth hormone metabolism and in biochemical markers of both bone and non-bone collagen synthesis was seen following incremental doses of GH in GHD.

Influence of the exercise protocol on hemodynamic, gas exchange, and neurohumoral responses to exercise in heart transplant recipients.

BACKGROUND: A gradual accommodation to increasing exercise loads has been recommended for exercise testing in denervated posttransplantation heart recipients. However, how the exercise protocol influence the hemodynamic, gas exchange, and hormonal response to exercise in this not been studied. METHODS: Nine heart transplant recipients tests incremental maximal bicycle ergometry tests in random order. Exercise stages of 1 and 3 minute durations were compared with matched work rate increments ranging between 30 and 40 W. Expiratory gas was measured continuously and arterial blood was sampled at each of the matched work rates. RESULTS: Total exercise duration was 6.4 +/- and 15.3 +/- 0.7 minutes for the 1-minute and 3-minute protocols, respectively. Maximal workload was significantly higher during the 1-minute versus the 3-minute protocol (238 +/- 9 versus 200 +/- 11 W, p < 0.001), but maximal oxygen uptake was not significantly different (25.5 +/- 1.1 versus 26.5 +/- 1.2 ml. min-1.kg-1). Hemodynamic, metabolic, and some hormonal parameters showed marked differences between the two protocols, with significantly higher responses observed during the 3-minute protocol for heart rate, ventilation, lactate, atrial natriuretic factor, and growth hormone. Catecholamine (epinephrine and norepinephrine) and insulin responses did not differ between the two tests. If expressed as a relative exercise intensity (percentage of maximal oxygen uptake) no differences in hormonal responses were observed between the two protocols, except for growth hormone response which remained higher during the 3-minute protocol. CONCLUSIONS: Although maximal oxygen uptake was independent of the exercise protocol in these heart transplant recipients, the exercise protocol has a major influence on the hormonal and metabolic response. The delayed response observed for oxygen uptake and hormonal responses suggests a significant physiologic lag time during the more rapidly incremental protocol. These differences should be taken into account when exercise is used as a method to evaluate the heart transplant recipient.

Collagen metabolism in two types of autosomal dominant osteopetrosis during stimulation with thyroid hormones.

In order to investigate collagen metabolism in two different types of autosomal dominant osteopetrosis (ADO), eight patients with type I (aged 23-61 years, mean 40.4 years) and nine patients with type II ADO (aged 20-49 years, mean 32.8 years) were compared with ten normal controls (aged 22-54 years, mean 35.4 years). The subjects were treated with 100 micrograms of triiodothyronine (T3) daily for 7 days and followed for a total of 4 weeks. Serum T3 increased in all subjects and a corresponding suppression of thyroid-stimulating hormone (TSH) was observed. Serum carboxy-terminal propeptide of type I collagen (S-PICP) in the control and type I groups showed no difference at baseline, whereas type II was lower than controls (p < 0.01). No significant alterations following stimulation were observed in any of the groups. Serum BGP (osteocalcin) values in the two patient groups were insignificantly lower than controls both at baseline and throughout the study. Following stimulation, a significant response was seen in the three groups (p < 0.001). The increases during the treatment period (delta values) for controls, type I and type II were 47.6% (p < 0.01), 51.7% (p = 0.05) and 34.8% (NS), respectively, with no difference between the groups. Serum bone-specific alkaline phosphatase (S-ALP) was not different between the groups and no alterations were observed in relation to treatment. The serum N-terminal propeptide of type III collagen (S-PIIINP) showed no difference at baseline between type I and controls but was significantly higher (p < 0.003) in type II than in the controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of sequential hormone replacement therapy in the treatment of hypercholesterolaemia among postmenopausal women.

OBJECTIVES: To test the efficacy of hormone replacement therapy (HRT) and dietary therapy, compared to dietary therapy, in lowering LDL cholesterol levels among postmenopausal women. DESIGN: A prospective parallel randomized study of sequential 17 beta-oestradiol and norethisterone acetate or placebo for 48 weeks. SETTING: A University outpatient lipid clinic. SUBJECTS: A total of 76 postmenopausal women, aged 43-60 years, with LDL cholesterol levels > or = 4.2 mmol 1-1, treated with a lipid-lowering diet. MAIN OUTCOME MEASURES: Levels of lipids, lipoproteins, apolipoproteins, fibrinogen and glucose tolerance. RESULTS: Adherence to the diet was similar in both groups. Total and LDL cholesterol levels were reduced by 14% (95% CI, 11-17%) and 19% (95% CI, 14-23%), respectively, in the HRT group vs. 3% (95% CI, 0-7%) and 5% (95% CI, 0-11%) in the diet group. HRT reduced the levels of apolipoprotein B and lipoprotein(a). Levels of HDL cholesterol, HDL2, HDL3, triglycerides, lipoprotein populations and apolipoproteins AI and AII remained unchanged. No adverse effects on glucose tolerance or on fibrinogen levels were observed. The reduction in LDL cholesterol was positively correlated with initial levels of LDL cholesterol and negatively correlated with body mass index. CONCLUSIONS: HRT is effective in reducing elevated LDL cholesterol levels, and should be considered in the treatment of hyperlipidaemic postmenopausal women, in addition to dietary therapy.

A comparison of octreotide, bromocriptine, or a combination of both drugs in acromegaly.

We investigated the pharmacokinetics of bromocriptine and octreotide, both individually and in combination, in 12 patients with active acromegaly. The pharmacodynamics of the drugs were assessed by 12-h profiles of GH secretion and insulin-like growth factor-I (IGF-I) measurements. During the 42-day study period, bromocriptine was administered for 28 days (from day 8; 5 mg, orally, twice daily) and octreotide (200 micrograms, sc, twice daily) from days 15-42. IGF-I levels, 12-h GH, and plasma bromocriptine and octreotide profiles were obtained on days 0, 14, 28, and 42. During bromocriptine treatment, both the area under the GH day curves (AUC) and mean IGF-I decreased to 64% (95% confidence limits, 43-72% and 48-82%, respectively) of initial values. During octreotide treatment, the respective values were 23% (18-30%) and 32% (21-36%), which were greater decreases than those during bromocriptine treatment [36% (95% confidence limits, 32-54%) for AUC for GH and 50% (95% confidence limits, 34-58%) for IGF-I]. With combined treatment, the AUC for GH was reduced to 16% (12-21%) and that of IGF-I to 25% (16-27%) of initial values. This combination was more effective than bromocriptine [25% (95% confidence limits, 22-37%) for AUC for GH and 39% (95% confidence limits, 25-43%) for IGF-I] and octreotide alone [78% (95% confidence limits, 53-89%) for AUC for GH and 78% (95% confidence limits, 57-98%) for IGF-I]. The pharmacokinetic parameters of octreotide were unchanged by the coadministration of bromocriptine. The bioavailability of bromocriptine increased by approximately 40% when bromocriptine was administered together with octreotide compared with administration alone (P < 0.01). Bromocriptine disposition parameters were unaltered. In conclusion, treatment of acromegalics with a combination of octreotide and bromocriptine increases the bioavailability of bromocriptine and reduces both GH and IGF-I levels more effectively than treatment with either drug alone. This presents the possibility of less frequent drug administrations, lower doses of octreotide, and, consequently, lower treatment costs.

Long-term treatment of macroprolactinomas with CV 205-502.

The long-term efficacy and tolerability of CV 205-502, a non-ergot dopamine agonist with D-2 receptor affinity, were studied for up to 36 months in 16 patients with macroprolactinomas. Prolactin values were reduced in all cases, becoming either normalized or suppressed in 12. The pituitary tumor size was reduced in the 13 patients with an obvious tumor and visual function normalized in all six patients with initial defects. Concomitantly we observed improvement in gonadal function, galactorrhea, headache, libido and general well-being. Adverse reactions were experienced by 15 patients during dosage increment and caused one patient to discontinue the medication. Seven patients had persistent adverse effects which prohibited a dosage increase of CV 205-502, sufficient to normalize PRL levels in three. Two patients experienced serious adverse events, causing the discontinuation of treatment in one case. In eight patients treatment with CV 205-502 and bromocriptine could be compared. Three patients responded better to CV 205-502 than to bromocriptine treatment. Only one patient preferred bromocriptine to CV 205-502 for long-term treatment. We conclude that CV 205-502 is an effective and in most cases well-tolerated treatment for patients with macroprolactinomas. CV 205-502 is preferable to bromocriptine as an initial treatment and should also be tried in patients where treatment with bromocriptine has failed.

Persistence of hyperinsulinemia in polycystic ovary syndrome after ovarian suppression by gonadotropin-releasing hormone agonist.

To investigate the effect of long-term androgen suppression on insulin sensitivity, obese and non-obese women with the polycystic ovary syndrome and obese and non-obese ovulatory women were given an oral glucose tolerance test before and after treatment with a gonadotropin-releasing hormone agonist. The women with polycystic ovary syndrome showed higher basal luteinizing hormone and androgen levels than the ovulatory women. All women with the polycystic ovary syndrome responded non-diabetically to the glucose tolerance test. However, compared with controls, the obese women with the polycystic ovary syndrome showed a hyperinsulinemic response to the glucose tolerance test, indicating insulin resistance. During the 3-h glucose tolerance test there was no concomitant change in androgen levels in the hyperinsulinemic women with the polycystic ovary syndrome. The insulin response to an oral glucose tolerance test remained unchanged in all women, although a hypogonadotropic hypogonadal state was maintained for several weeks. This study therefore suggests that endogenous androgens do not play a role in sustaining insulin resistance in women with the polycystic ovary syndrome.

Effects of short-term treatment with naproxen on kidney function in insulin-dependent diabetic patients with microalbuminuria.

The renal effects of the prostaglandin synthesis inhibitor naproxen was investigated in eight patients with incipient type I diabetes nephropathy. The patients were treated with 1000 mg naproxen daily for 4 days in a placebo-controlled double-blind cross-over study. Naproxen reduced urinary prostaglandin E2 (PGE2) excretion by 60%, from 276 ng/24 h to 110 ng/24 h (P less than 0.05). Plasma renin activity (PRA) was reduced by 45% (P less than 0.05). Glomerular filtration (GFR) (single bolus 99mTc-DTPA technique) and effective renal plasma flow (ERPF) (131I-Hippuran clearance) were unchanged by naproxen. Microalbuminuria and renal albumin clearance was unchanged as was also urinary excretion of sodium, glandular kallikrein and beta 2-microglobulin (beta 2-M). Our results show that albumin excretion in incipient diabetic nephropathy is not solely dependent on the renal prostaglandin system. The difference in action between naproxen in this study and indomethacin in previous reports, could be caused by renal actions of indomethacin independent of the prostaglandin system.