Endocrine and metabolic aspects of the Wolfram syndrome.

Wolfram syndrome (WS), also known as DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness), is a neurodegenerative disease with autosomal recessive inheritance with incomplete penetrance. DIDMOAD is a very rare disease with an estimated prevalence of 1 in 770,000 and it is believed to occur in 1 of 150 patients with juvenile-onset insulin-dependent diabetes mellitus. Additionally, WS may also present with different endocrine and metabolic abnormalities such as anterior and posterior pituitary gland dysfunction. This mini-review summarizes the variable presentation of WS and the need of screening for other metabolic and hormonal abnormalities, coexisting in this rare syndrome.

Anxiety is associated with hormonal and metabolic profile in women with polycystic ovarian syndrome.

BACKGROUND: Increased prevalence of psychological morbidities, including anxiety, depression and eating disorders, has been reported in women with polycystic ovary syndrome (PCOS) in comparison with normal ovulating, nonhyperandrogenemic women. AIM OF THE STUDY: To investigate the relationship between the degree of anxiety, depression and eating disorders via self-reported symptoms and the severity of hormonal and metabolic aberrations in women with PCOS. For this purpose, the PCOS cohort was subdivided into three subgroups according to the degree of anxiety. METHODS: One hundred and thirty women with PCOS of similar age and BMI were studied. In each subject, hormonal and metabolic status as well as psychological profile was assessed with the use of specific questionnaires. Specifically, anxiety (trait and state) was assessed with the use of STAI-T and STAI-S, while depression and eating disorders were evaluated with the use of the Beck Depression Inventory and the Eating Attitudes test, respectively. RESULTS: The subgroups did not differ in age and BMI. Subjects with the highest STAI-S compared with those with the lowest STAI-S displayed significantly higher the homeostasis assessment model-insulin resistance (HOMA-IR) and free androgen index values (P < 0·05), respectively. Regarding trait anxiety, assessed by STAI-T, HOMA-IR values were significantly elevated (P < 0·05) in the subgroup with the higher STAI-T score compared with the HOMA-IR in the group with the lower STAI-T score. CONCLUSIONS: In women with PCOS, the degree of anxiety, state and trait (STAI-S, STAI-T) appears to vary in a pattern similar to that of hyperandrogenemia and insulin resistance, independently of age and BMI. The pathophysiological mechanisms underlying the association of psychological morbidities with androgen excess and insulin resistance in PCOS remain to be elucidated.

The pluripotential effects of hypolipidemic treatment for polycystic ovary syndrome (PCOS): dyslipidemia, cardiovascular risk factors and beyond.

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome characterized by oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenemia and polycystic ovaries. Clinical expression is determined by both genetic and environmental factors. Dyslipidemia is very common in lean as well as in obese women with PCOS and should be considered in the therapeutic management of the syndrome. Additionally to dyslipidemia, other risk factors for cardiovascular disease strongly associated with PCOS include insulin resistance, impaired glucose tolerance and metabolic syndrome. Therefore, the ideal therapeutic approach for PCOS would be multi targeted treatment ameliorating not only ovarian dysfunction but also cardiometabolic aspects, including dyslipidemia. Recently, a new era of hypolipidemic agents like statins has been initiated with regard to PCOS. The spectrum of statins' targets has been expanded and in vitro and in vivo studies have explored the specific effect of statins on androgen production, insulin resistance and inflammatory markers in PCOS. Statins are potentially promising therapeutic agents targeting hormonal and metabolic disturbances in PCOS, though conclusive results are still pending. Since several hormonal and metabolic aberrations characterizing this multifaceted syndrome cluster and interact with each other, their effects on the lipid profile are interweaving and the therapeutic modalities targeting dyslipidemia appear to have a more broad beneficial effect.

Strong and positive association of endothelin-1 with AGEs in PCOS: a causal relationship or a bystander?

OBJECTIVE: Advanced glycation end products (AGEs) activate the intracellular Nuclear Factor-κB pathway in endothelial cells, leading to production of endothelin-1 (ET-1), a peptide which causes endothelial dysfunction. The aim of the present study was to assess ΕΤ-1 and AGEs levels in women with polycystic ovary syndrome (PCOS) and controls and to investigate any potential relationship between them. DESIGN: Metabolic and hormonal data from 75 women with PCOS and 25 controls, matched for age and ΒΜΙ were analyzed and correlated to AGEs and ET-1 levels. RESULTS: Serum levels of ΕΤ-1 (1.55±0.13 vs. 0.37±0.10 pmol/l, p:0.003) and AGEs (8.34±1,81 vs. 5.77±0.78U/ml, p:0.002) were significantly higher in the PCOS group. ΕΤ-1 was correlated with AGES (r:0.54, p<0.001), Testosterone (r: 0.38, p<0.001), ΔΑ4 (r: 0.41, p<0.001) and FAI (r: 0.21, p<0.05). However, multiple linear regression analysis in the total study population showed that ΕΤ-1 was positively associated only with AGES (ß: 0.22, p<0.001). CONCLUSIONS: ET-1 levels were positively and strongly associated with AGEs in both PCOS women and controls, suggesting that the detrimental effect of AGEs on endothelial cells may involve increased ET-1 production.

Liver failure due to antithyroid drugs: report of a case and literature review.

Hyperthyroidism is a common endocrine disorder affecting 2% of females and 0.5% of males worldwide and antithyroid drugs constitute the first line of treatment in the majority of cases. These agents may cause severe adverse effects and among them liver failure, although rare, is a potential lethal one. This case illustrates the sudden and abrupt deterioration of hepatic function due to antithyroid drug administration. This case along with a concise literature review is presented aiming to increase the awareness of endocrinologists of possible fatal complications from the everyday use of common agents such as antithyroid drugs.

Metformin in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) affects 6.6-6.8% of women in reproductive age. Insulin resistance and hyperinsulinemia play a critical role in the pathogenesis of PCOS and are associated with a high risk for type 2 diabetes mellitus and cardiometabolic abnormalities. Metformin has been introduced as a therapeutic option in PCOS, targeting of cardiometabolic and reproductive abnormalities on the basis of its action on the reduction of glucose levels and the attenuation of insulin resistance. The tissue-specific actions of metformin as well as the molecular mechanisms involved in the liver, the muscle, the endothelium, and the ovary are elucidated in this review. The use of metformin in pregnant women with PCOS is another of its positive features. Overall, available data supports the therapeutic usefulness of metformin on cardiometabolic risk and reproduction assistance in PCOS women.

Androgens associated with advanced glycation end-products in postmenopausal women.

OBJECTIVE: Higher frequency of subclinical atherosclerosis has been linked with androgen levels in postmenopausal women. Advanced glycation end-products (AGEs) are well-recognized atherogenic molecules. Therefore, we investigated the association of postmenopausal sex steroid and metabolic status with serum AGE levels. METHODS: Serum sex hormones, fasting glucose, fasting insulin, and AGEs were assessed in 106 healthy postmenopausal women. Insulin resistance was estimated by using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Women in the highest testosterone quartile (Q4) had higher serum AGE levels (Q1, 5.22 IU/mL ± 0.50; Q2, 5.08 ± 0.53 IU/mL; Q3, 5.78 ± 1.10 IU/mL vs Q4, 7.35 ± 1.23 IU/mL; P < 0.0005) compared with women in the lowest testosterone quartiles. Accordingly, women in the highest free androgen index (FAI) quartile had higher serum AGE levels (Q1, 5.36 ± 0.59 IU/mL; Q2, 5.28 ± 0.72 IU/mL vs Q4, 6.68 ± 1.48 IU/mL; P < 0.0005) compared with women in the lowest FAI quartile. These findings remained significant after adjustment for age, body mass index, HOMA-IR, and fasting glucose and fasting insulin levels. A highly significant correlation was found for testosterone and FAI with AGEs and persisted after adjustment for age, body mass index, HOMA-IR, and fasting glucose and fasting insulin levels (r = 0.67, P < 0.0005) CONCLUSIONS: The data from the current study suggest that higher levels of AGEs are positively associated with higher androgen levels. This association, identified for the first time, may provide an additional insight into the pathophysiological mechanisms linking the described higher prevalence of cardiovascular events with higher androgen levels in postmenopausal women.

Metformin: an old medication of new fashion: evolving new molecular mechanisms and clinical implications in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is now recognized to be the most common endocrinopathy in women of reproductive age with a prevalence of 6.6-6.8%. PCOS, a syndrome of unknown etiology, was initially regarded as a reproductive disorder. However, in the last 15 years the role of insulin resistance (IR) has been identified as a significant contributor to the pathogenesis of PCOS, and the metabolic and cardiovascular sequelae of the syndrome have been increasingly appreciated. The coexistence and interaction of reproductive and cardiometabolic abnormalities in the context of PCOS have created a need for a modified therapeutic management of affected women. Insulin sensitizers, particularly metformin, have been introduced as a pharmaceutical option targeting not only IR, but several other aspects of the syndrome, including reproductive abnormalities. The landscape of the multifaceted actions of metformin evolves to broaden the therapeutic implications of this old drug in a new fashion for patients with PCOS. Most recently, the spectrum of metformin's targets has been expanded, and molecular studies have explored the tissue-specific mechanisms of metformin in the liver, the muscle, the endothelium, and the ovary. The use of metformin in pregnant women with PCOS comprises another scarcely explored, but promising area of research. This review attempts to cover the spectrum of metformin's cellular actions in different tissues and to summarize the current literature regarding the potential medical value of this medication in PCOS. Even if many of these actions are individually modest, they seem to be collectively sufficient to confer therapeutic benefits not only in cardiometabolic aspects but also in reproductive aspects of PCOS.

In overweight/obese but not in normal-weight women, polycystic ovary syndrome is associated with elevated liver enzymes compared to controls.

OBJECTIVE: To investigate liver enzymes in a cohort of women with Polycystic Ovary Syndrome (PCOS) and controls divided according to body mass index (BMI) and their association with features of the syndrome. DESIGN: Eighty-three PCOS women and 64 healthy women were studied. Patients and controls were subdivided into two groups, a lean subgroup (BMI <25kg/m(2)) and an overweight/obese subgroup (BMI >25kg/m(2)). Clinical history, height and weight were obtained and metabolic and hormonal parameters were determined. RESULTS: Serum fasting insulin, fasting glucose, HOMA-IR, triglycerides and total cholesterol were significantly higher (p<0.05) in women with PCOS compared to controls. No significant difference in serum liver enzymes levels between PCOS women and controls was detected. However, serum levels of alanine aminotransferase (ALT) (17.7 vs. 14.1 U/L, p<0.05) and gamma-glutamyl transpeptidase (gammaGT) (17.9 vs. 13.4 U/L, p<0.05) were significantly higher in overweight/obese PCOS women compared with overweight/obese controls. In overweight/obese PCOS patients and controls, ALT levels were positively correlated with free androgen index (FAI) (r=0.25 p<0.05) and total testosterone levels (r=0.33 p<0.01). CONCLUSIONS: The finding of elevated liver enzymes in overweight/obese PCOS women raises the question of screening for non-alcoholic fatty liver disease in this group.

Hyperreninemia characterizing women with polycystic ovary syndrome improves after metformin therapy.

BACKGROUND: Polycystic ovary syndrome (PCOS) is characterized by chronic anovulation, hyperandrogenemia and insulin resistance. Hyperreninemia is observed in insulin resistance and hyperandrogenemic states. AIMS: To investigate the levels of total plasma renin and their possible relationship with insulin resistance and hyperandrogenemia and to explore the effect of metformin on these parameters in PCOS women. METHODS: 48 PCOS women who were age- and body mass index (BMI)-matched with 21 healthy women were studied. Total renin, aldosterone levels, glucose and insulin levels were measured at basal state and during an oral glucose tolerance test in all subjects. A subgroup of women with PCOS was evaluated 6 months after metformin administration. RESULTS: Total renin levels were significantly higher in PCOS women compared to controls. PCOS women compared to controls displayed higher areas under the curve for glucose, insulin and total renin (AUCREN). Mean AUCREN was correlated significantly with insulin resistance indices and positively with free testosterone levels. Total renin, aldosterone, androgen levels and insulin sensitivity indices were significantly improved after 6 months on metformin treatment. CONCLUSIONS: PCOS women demonstrated an insulin resistance and hyperandogenemia-related increase in serum total renin levels. Metformin treatment was shown to significantly reduce total renin levels.

Defects in insulin signaling pathways in ovarian steroidogenesis and other tissues in polycystic ovary syndrome (PCOS).

The polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age today. Women with PCOS often demonstrate defective ovarian steroid biosynthesis and present with hyperandrogenemia. Moreover, 50-70% of PCOS women are insulin resistant and hyperinsulinemic. Insulin acts on the ovary via its own receptor and interacts with gonadotrophins, modulating steroidogenesis. The precise role of insulin and the molecular mechanisms that take place are not yet completely explicated. This review will be focused on insulin's action on the ovary and other target tissues, describing the intracellular signaling pathways implicated in steroidogenesis and their defects in women with PCOS.

Stress in women: metabolic syndrome and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a heterogeneous syndrome that is characterized from oligo- or anovulation, clinical and/or biochemical signs of hyperandrogenism, and polycystic ovaries. Clinical expression is determined by genetic as well as environmental factors. Women with PCOS are a specific group of women which have several aspects of metabolic syndrome (MBS). Concomitantly MBS could be part of metabolic abnormalities present in PCOS. Stress has been linked to aggravate the metabolic abnormalities present in MBS. An interaction seems to exist between stress, environmental, as well as genetic factors, starting from the prenatal age and continuing to the adult life. This results in specific endocrinological and metabolic disorders which are shared by women with PCOS and women with MBS.

Primary adrenal lymphoma presented with adrenal insufficiency.

We report a 71-year old man who presented with symptoms of adrenal insufficiency and large bilateral adrenal masses. Computed tomography guided FNA biopsy was not diagnostic. However, because of the rapid growth of the masses, the negative workup for primary malignancy and the strong clinical suspicion of a lymphoma, an open biopsy was performed and a B-cell lymphoma was disclosed.