Dopamine Agonists as a Novel "Cure" for Autoimmune Diabetes.

We present a patient who, when treated for macroprolactinoma with a dopamine agonist (DA), was able to stop insulin treatment of his autoimmune diabetes for 2 years. The patient was diagnosed with autoimmune diabetes after presenting to emergency services in diabetic ketoacidosis aged 50 years. On presentation, he had high titers of autoantibodies associated with pancreatic islet cell destruction and a high level of glycated hemoglobin. On review in the endocrinology clinic, he displayed signs and symptoms of hypogonadism. Subsequent investigations revealed low testosterone and high prolactin with a pituitary macroadenoma on magnetic resonance imaging. He was diagnosed with a macroprolactinoma and treated with DA. This treatment reversed his insulin requirement and he achieved excellent glycemic control without any hypoglycemic agent. At this point, his diagnosis was revised to latent autoimmune diabetes of adults. Two years after commencing the DA, insulin had to be restarted. We hypothesize that in addition to autoimmune destruction of the pancreatic ß cells, there were several other causes of hyperglycemia in this patient, including hyperprolactinemia and hypogonadism. The correct diagnosis led to significant weight loss and appropriate therapy, with a dramatic improvement in quality of life.

A novel assessment and treatment approach to patients with Hashimoto's encephalopathy.

Hashimoto's encephalopathy (HE) is rarely reported with only a few hundred cases published. Diagnosis is made in patients with an appropriate clinical picture and high antithyroperoxidase (anti-TPO) antibodies after infectious, toxic and metabolic causes of encephalopathy have been excluded. There is little objective data on the neurocognitive impairment in patients with HE and their improvement with treatment. We present the case of a 28-year-old woman with HE. Approach to management was novel as objective neuropsychological assessment was used to assess her clinical condition and response to treatment. Intravenous immunoglobulin (IVIg) as the first-line treatment instead of steroids. She responded well. The case illustrates that a different approach is required for the diagnosis and treatment of HE. A new diagnostic criteria is proposed that includes neurocognitive assessment, serum and CSF antibodies, an abnormal EEG and exclusion of other causes of encephalopathy. Furthermore, treatment should be tailored to the patient. LEARNING POINTS: Neurocognitive assessment should be carried out to assess the extent of brain involvement in suspected Hashimoto's encephalopathy pre- and post- treatment.Treatment of Hashimoto's encephalopathy should be tailored to the patient.Unifying diagnostic criteria for Hashimoto's encephalopathy must be established.

A Follow-Up Study of the Prevalence of Valvular Heart Abnormalities in Hyperprolactinemic Patients Treated With Cabergoline.

CONTEXT: Uncertainty exists whether the long-term use of ergot-derived dopamine agonist (DA) drugs for the treatment of hyperprolactinemia may be associated with clinically significant valvular heart disease and whether current regulatory authority guidelines for echocardiographic screening are clinically appropriate. OBJECTIVE: Our objective was to provide follow-up echocardiographic data on a previously described cohort of patients treated with DA for lactotrope pituitary tumors and to explore possible associations between structural and functional valve abnormalities with the cumulative dose of drug used. DESIGN: Follow-up echocardiographic data were collected from a proportion of our previously reported cohort of patients; all had received continuous DA therapy for at least 2 years in the intervening period. Studies were performed according to British Society of Echocardiography minimum standards for adult transthoracic echocardiography. Generalized estimating equations with backward selection were used to determine odds ratios of valvular heart abnormalities according to tertiles of cumulative cabergoline dose, using the lowest tertile as the reference group. SETTING: Thirteen centers of secondary/tertiary endocrine care across the United Kingdom were included. RESULTS: There were 192 patients (81 males; median age, 51 years; interquartile range [IQR], 42-62). Median (IQR) cumulative cabergoline doses at the first and second echocardiograms were 97 mg (20-377) and 232 mg (91-551), respectively. Median (IQR) duration of uninterrupted cabergoline therapy between echocardiograms was 34 months (24-42). No associations were observed between cumulative doses of dopamine agonist used and the age-corrected prevalence of any valvular abnormality. CONCLUSION: This large UK follow-up study does not support a clinically significant association between the use of DA for the treatment of hyperprolactinemia and cardiac valvulopathy.

A novel surgical approach for the management of giant invasive prolactinoma compressing the brainstem.

UNLABELLED: Prolactinomas constitute the largest subsection of all secretory pituitary adenomas. Most are microprolactinomas and are satisfactorily treated by medical management alone. Giant prolactinomas, measuring more than 4 cm in diameter, are rare and usually occur more commonly in men. Macroprolatinomas tend to present with symptoms of mass effect rather than those of hyperprolactinaemia. Dopamine agonists (DA) are the treatment of choice for all prolactinomas. Surgery is usually reserved for DA resistance or if vision is threatened by the mass effects of the tumour. We describe the case of a 52 year-old woman with a giant invasive prolactinoma who required multiple surgical procedures as well as medical management with DA. One of the surgical interventions required a posterior approach via the trans cranial sub occipital transtentorial approach, a surgical technique that has not been previously described in the medical literature for this indication. The giant prolactinoma was reduced significantly with the above approach and patient symptoms from the compressing effects of the tumour were resolved. This case highlights the importance of a multidisciplinary approach to the management of such patients who present with florid neurological sequelae secondary to pressure effects. Although this presentation is uncommon, surgery via a sub occipital transtentorial approach may be considered the treatment of choice in suitable patients with giant invasive prolactinomas compressing the brainstem. LEARNING POINTS: Giant prolactinomas present with symptoms of mass effect or those of hyperprolactinaemia.Interpretation of the pituitary profile is crucial to guide further investigations and management.Treatment of giant invasive prolactinomas may involve a combination of medical management and multiple surgical interventions.Treatment with DA may cause pituitary haemorrhage or infarction in patients with these tumours.A sub occipital transtetorial approach may be considered the treatment of choice in invasive prolactinomas compressing the brainstem.Multidisciplinary approach of such patients is fundamental for a better outcome.

Raised concentrations of lipid peroxidation products (LPO) in pregnant women with impaired glucose tolerance.

INTRODUCTION: Lipid peroxidation (LPO) results from oxidative damage to membrane lipids. Whereas LPO rises in normal pregnancy, the effect of gestational diabetes mellitus (GDM) on this process has not been clearly defined. MATERIALS AND METHOD: Fasting blood concentrations of malondialdehyde+4-hydroxyalkenals (MDA+4-HDA), as LPO index, TNFa soluble receptors (sTNF-R1 and sTNF-R2), and soluble adhesion molecules (sICAM-1, sVCAM-1), were measured in 51 women at 28 weeks of gestation. The women were divided according to the results of 50.0 g glucose challenge test (GCT) and 75.0 g oral glucose tolerance test (OGTT): Controls (n=20), normal responses to both GCT and OGTT; Intermediate Group (IG) (n=15), abnormal GCT but normal OGTT; GDM group (n=16), abnormal both GCT and OGTT. RESULTS: Glucose concentrations in women diagnosed with GDM were within the range of impaired glucose tolerance. There were no significant differences in concentrations of either TNF a soluble receptors R1 and R2, or sICAM-1 or sVCAM-1. LPO concentrations [MDA+4-HDA (nmol/mg protein)] were significantly higher in women with GDM than in the other two groups [64.1±24.3 (mean±SD), 39.3±23.1, 47.0±18.1, for GDM, IG and Controls, respectively; p<0.05]. In multivariate analysis, the only significant independent correlation was between LPO level and glucose at 120 minutes of OGTT (rs=0.42; p=0.009). CONCLUSIONS: Oxidative damage to membrane lipids is increased in GDM and might result directly from hyperglycaemia. Physiological significance of this phenomenon remains to be elucidated.

Normal vaginal flora, disorders and application of probiotics in pregnancy.

PURPOSE: To assess the effectiveness of vaginal administration of the probiotic Lactobacillus rhamnosus BMX 54 in preventing the occurrence of abnormal vaginal flora and the alteration of parameters relevant to the progression of pregnancy. METHODS: Sixty pregnant women were assigned randomly to the untreated arm of the study (n = 30) or received (n = 30) vaginal application of one tablet containing Lactobacillus rhamnosus BMX 54, once a week for 12 weeks. Every 4 weeks (T0-T3), vaginal and cervical swabs were collected and pH, and quantity and quality of vaginal discharge measured as well as consistency, length and dilatation of cervix, and level of the presenting part of the foetus relative to interspinous diameter. RESULTS: In untreated women, there was a significant trend towards increase in the presence of pathogenic microorganisms in the vaginal and/or cervical swabs (p < 0.05), and in average pH values (p < 0.05), amount (p < 0.05) and "whiff test" positivity (p < 0.05) of vaginal discharge. Significant trend was also found for decrease in length (p < 0.0001) and increase in dilatation (p < 0.05) of cervix, as well as for lower position of the foetus (p < 0.0001). In the group treated with Lactobacillus rhamnosus BMX 54, none of these values significantly changed throughout the observation period, with the exception of cervical length that was significantly decreased at T3 (p < 0.01). CONCLUSIONS: During pregnancy, vaginal administration of Lactobacillus rhamnosus BMX 54 is effective in preventing the development of abnormal vaginal microflora, lowering of the presenting part of the foetus and modifying cervical parameters that could represent risk factors of vulnerability to preterm delivery.

Serum levels of matrix metalloproteinases MMP-2 and MMP-9 and their inhibitors in women with glucose intolerance in pregnancy and normal controls.

AIM: Matrix metalloprotenases (MMPs) are proteolytic enzymes active in inflammatory states. We have examined MMP-9, MMP-2, and their respective tissue inhibitors: TIMP-1 and TIMP-2 in sera of women with gestational diabetes mellitus (GDM) and various degrees of insulin resistance (IR) in the third trimester of pregnancy. METHODS: Fasting serum levels of MMP-9, MMP-2, TIMP-1 and TIMP-2 were measured in 26th-28th week of gestation in 51 women divided according to their response to a 50-g glucose challenge test (GCT) and a 75-g OGTT: controls (n = 20): both tests normal; the GDM group (n = 16) both tests abnormal; the intermediate group (IG; n = 15) abnormal GCT and normal OGTT. MMPs and TIMPs were correlated with the parameters of IR: homeostasis model assessment (HOMA) and insulin resistance index (IRI). RESULTS: MMP-9, MMP-2, TIMP-1 and MMP-9/TIMP-1 ratio were not different among the groups. TIMP-2 levels were significantly higher in the GDM and IG groups than in controls (p < 0.01). MMP-2/TIMP-2 ratio was lower in the GDM group than in the other groups (p < 0.01) and was correlated to HOMA and IRI (r = -0.465 and r = -0.43 respectively, p < 0.01). CONCLUSIONS: Serum MMP levels do not reflect inflammation in GDM. Elevated TIMP-2 and consequently lower MMP-2/TIMP-2 levels in GDM need to be clarified, but are unlikely to be a consequence of inflammation.

Elevated concentrations of retinol-binding protein-4 (RBP-4) in gestational diabetes mellitus: negative correlation with soluble vascular cell adhesion molecule-1 (sVCAM-1).

BACKGROUND: Retinol-binding protein-4 (RBP-4) may increase insulin resistance (IR) in animals, with elevated levels reported in humans with obesity and type 2 diabetes. There are, however, few data on concentrations of RBP-4 in gestational diabetes mellitus (GDM). METHODS: We measured fasting serum levels of RBP-4, soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in 50 women at 28 weeks of gestation, divided according to the results of a 50 g glucose challenge test (GCT) and a 75 g oral glucose tolerance test (OGTT): (1) controls (n = 20), normal responses to both GCT and OGTT; (2) intermediate group (IG) (n = 15): false positive GCT, but normal OGTT; and (3) GDM group (n = 15), both GCT and OGTT abnormal. IR was assessed by homeostasis model assessment (HOMA-IR) and by insulin resistance index (IRI) based on glycemia and insulinemia during OGTT. RESULTS: All groups were matched for age and body mass index (BMI). RBP-4 levels (microg/ml, mean+/-standard deviation) were higher in women with GDM vs. controls (53.9 +/- 17.9 vs. 29.7 +/- 13.9, p < or = 0.001), with a trend towards higher RBP-4 in GDM compared with IG (38.0 +/- 19.3, p = 0.07). There was no significant correlation between RBP-4 and age, BMI, insulin, IRI or HOMA-IR, but there was a moderate, significant negative correlation between RBP-4 and sVCAM-1 (r(2) = 0.20, p = 0.001). CONCLUSIONS: RBP-4 levels are elevated in women with GDM, but do not correlate with IR indices and correlate negatively with sVCAM-1. The physiological significance of RBP-4 rise in women with GDM remains to be elucidated.

Gelatinase A (MM-2), gelatinase B (MMP-9) and their inhibitors (TIMP 1, TIMP-2) in serum of women with endometriosis: Significant correlation between MMP-2, MMP-9 and their inhibitors without difference in levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in relation to the severity of endometriosis.

Endometriosis is a highly prevalent gynecological condition, where the formation of endometriotic foci is linked with locally increased activity of matrix metalloproteinases (MMPs). In the present study, we tested the hypothesis that raised serum levels of MMPs might reflect the severity of endometriosis. We compared serum levels of MMP-2 and MMP-9, and of their tissue inhibitors TIMP-1 and TIMP-2, in infertile women, matched for age and body mass index, with either mild (stage I, END-I; n = 15) or severe endometriosis (stage IV, END-IV; n = 22). There was no difference in the concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 between the analyzed groups. There was, however, a correlation between MMP-9 and TIMP-1 for the combined group (n = 37) (r = 0.48; p = 0.0032) and in women with END-IV (r = 0.51; p = 0.0163), as well as a highly significant correlation between MMP-2 and TIMP-2 for the combined group (r = 0.69; p = 0.0001), END-I (r = 0.51; p = 0.0406) and END-IV groups (r = 0.77; p = 0.0001). There was also a significant correlation between TIMP-1 and TIMP-2 in the combined and END-IV groups (r = 0.39; p = 0.0182 and r = 0.5450; p = 0.0099, respectively). The balance between MMPs and their inhibitors is preserved in the serum of women with endometriosis, but serum concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 cannot be considered to represent a valid measure of the severity of endometriosis.