DIAGNOSIS OF ENDOCRINE DISEASE: Drug-induced endocrinopathies and diabetes: a combo-endocrinology overview.

In the currently overwhelming era of polypharmacy, the balance of the dynamic and delicate endocrine system can easily be disturbed by interfering pharmaceutical agents like medications. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the feedback axis, on hormonal transport, binding and signaling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can interfere with the hormonal assays, leading to erroneous laboratory results that disorientate clinicians from the right diagnosis. The purpose of this review is to cover a contemporary topic, the drug-induced endocrinopathies, which was presented in the monothematic annual Combo Endo Course 2018. This challenging part of endocrinology is constantly expanding particularly during the last decade, with the new oncological therapeutic agents, targeting novel molecular pathways in the process of malignancies. In this new context of drug-induced endocrine disease, clinicians should be aware that drugs can cause endocrine abnormalities via different mechanisms and mimic a variety of clinical scenarios. Therefore, it is extremely important for clinicians not only to promptly recognize drug-induced hormonal and metabolic abnormalities, but also to address the therapeutic issues for timely intervention.

Novel strategies in the management of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting reproductive-aged women. PCOS has been recognized as a syndrome combining reproductive and metabolic abnormalities with lifelong health implications. Cardiometabolic alterations require regular screening and effective and targeted lifestyle advice to lose weight as well as to prevent weight gain. Pharmacological therapy includes insulin-sensitizer drugs and agents that act directly on metabolic comorbidities, such as statins and antiobesity drugs. Bariatric surgery may be an option for severely obese women with PCOS Regarding reproductive aspects, ovulation induction with antiestrogens such as clomiphene citrate or letrozole is the first-line medical treatment. Exogenous gonadotropins and in vitro fertilization (IVF) are recommended as second-line treatment for anovulatory infertility. Laparoscopic ovarian diathermy may be used in special cases and metformin is no longer recommended for ovulation induction. Combined oral contraceptives (OCs) are the first-line treatment for the management of menstrual irregularities in women not seeking pregnancy, also providing endometrial protection and contraception. Progestin-only pills or cyclical progestins are recommended for those with contraindications to OCs. Metformin is also considered a second-line choice for improving menstrual cycles in women presenting insulin-resistance and dysglicemia. Hirsutism requires cosmetic procedures and medical treatment with OCs. More severe cases may need anti-androgen drugs added to the OCs. In conclusion, strategies regarding the management of reproductive issues in PCOS encompass a tailored approach to individual needs of each patient.

Industrial endocrine disruptors and polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a complex and enigmatic syndrome of unknown origin and etiology enclosing a broad spectrum of phenotypic manifestations. PCOS pathophysiology combines reproductive and metabolic abnormalities into a heterogeneous disorder that has pervasive and devastating health consequences. Inquiring the generative roots of the syndrome, it has become increasingly apparent the role of the environment as a determinant factor. Experimental exposure to industrial endocrine disruptors has been related with the impairment of normal reproductive function and metabolic regulation possibly favoring the development of or aggravating PCOS-resembling clinical disorders. Industrial chemicals may reflect the contributing role of an unfavorable environment to unveil PCOS characteristics in genetically predisposed individuals or further deteriorate the hormonal and fertility imbalances of PCOS-affected females.

Multiple tuberculous abscesses and mediastinal lymphadenitis with no pulmonary involvement in an immunocompetent patient.

Tubercular cold abscesses secondary to neighbouring bone involvement are a well-known clinical manifestation of extra-pulmonary tuberculosis. However, primary soft tissue tuberculous abscesses with no pulmonary involvement in immuno-competent patients are very uncommon. A rare case of multiple primary intrathoracic and extraperitoneal soft tissue tuberculous abscesses and mediastinal lymph node tuberculosis with no pulmonary involvement is reported. This case demonstrates the need for a high index of suspicion for such rare presentations of extra-pulmonary tuberculosis in patients from endemic areas.

"Menstrual irregularities in PCOS. Does it matter when it starts?".

BACKGROUND: PCOS is presented by a broad spectrum of menstrual irregularities appearing often at puberty or later on during the reproductive years in women suffering from this multifaceted syndrome. To our knowledge, there is no evidence to suggest whether the time of onset of menstrual irregularities (peri or post pubertal) indicates a differential metabolic and/or hormonal profile as well as ovarian ultrasonographic findings, in adulthood in women with PCOS. AIM OF THE STUDY: To compare anthropometric, hormonal-metabolic profile and ultrasound findings in PCOS women with peripubertal onset of menstrual disorders with the corresponding data obtained from PCOS patients with post pubertal onset of menstrual irregularities, matched for BMI and age. PATIENTS-METHODS: 89 PCOS women were evaluated cross-sectionally at the age of 25 years. In 49 subjects menstrual irregularities were present from menarche, whereas in 40 women the irregularities appeared at least 3 years post menarche. RESULTS: Anthropometric parameters were comparable between the 2 groups. The 2 groups did not differ on metabolic and hormonal profile as well as ovarian ultrasound findings. CONCLUSIONS: These data indicate that the timing of menstrual irregularities, do not appear to have an impact, on hormonal/metabolic profile and ovarian ultrasound morphology in patients diagnosed with PCOS, later in life.

The role of kisspeptin/GPR54 in the reproductive system.

The Kiss-1 gene encodes a secreted protein that is proteolytically cleaved to produce a number of structurally related peptides, with high interspecies conservation, globally termed kisspeptins. The original niche for the role of kisspeptin in human physiology is derived from cancer biology, with the loss of Kiss-1 expression being associated with poor prognosis in several malignancies. However, kisspeptin has recently emerged as a fundamental player in the field of reproductive biology. Genetic analysis of large consanguineous pedigrees by two independent groups led to the association of inactivating mutations of GPR54, the receptor which mediates kisspeptin action, with idiopathic hypogonadotropic hypogonadism. In the present paper the most salient aspects of the multifaceted role of kisspeptin in the reproductive system are reviewed, including the association of kisspeptin with the gonadal steroid feedback loop and the triggering of puberty onset.

Peroxisome proliferator-activated receptor-γ and -δ polymorphisms in women with polycystic ovary syndrome.

The aim of the study was to examine the frequency and relationship of peroxisome proliferator-activated receptor (PPAR)-γ and PPAR-δ gene polymorphisms to polycystic ovary syndrome (PCOS) characteristics. We conducted a case-control study protocol, which included 183 PCOS women and 148 healthy volunteers. Genetic, clinical, hormonal, and metabolic characteristics of PCOS patients and controls were estimated and compared. Genotype and allele frequencies did not differ significantly. The Pro(12) Ala polymorphism in exon 2 of the PPAR-γ gene was found in low frequency. Regarding the polymorphism in exon 6, the T-allele carrier PCOS women had significantly lower total testosterone levels. Regarding the +294T/C polymorphism in the exon 4 of the PPAR-δ gene, the C-allele carrier PCOS women had significantly higher fasting glucose levels. In conclusion, the PPAR-γ gene polymorphisms do not appear to affect the risk for PCOS, except for the reduced testosterone levels. The +294T/C polymorphism in the exon 4 of the PPAR-δ gene seems to cause an increase in fasting glucose levels.

The impact of endocrine disruptors on endocrine targets.

Endocrine disruption represents one of the most controversial environmental issues of our époque. So far, many substances, both natural and artificial, have been recognized to interfere with endocrine signaling pathways. In intact laboratory animals, this interaction has been documented to generate adverse health outcomes by impairing normal functions. With regard to humans, evidence is limited and inconsistent to clearly establish a causal inference, however, accumulating data incriminate endocrine disrupting chemicals to reproductive disorders and disturbed thyroid homeostasis. Recently, as a result of animal models and preliminary human studies, a new area of interest has arisen concerning the implication of endocrine disruptors in the etiology of obesity and diabetes, the two major, life-threatening, epidemics of modern world. This article reviews the evidence linking endocrine disrupting chemicals to a broad spectrum of clinical perturbations from reproduction and thyroid to metabolic regulation.

CD40 expression and its association with low-grade inflammation in a Greek population of type 1 diabetic juveniles: evidence for differences in CD40 mRNA isoforms expressed by peripheral blood mononuclear cells.

BACKGROUND: CD40 signalling has been associated with the pathogenesis of autoimmune diseases and diseases with low-grade chronic inflammation. OBJECTIVE: To investigate, early in the course of type 1 diabetes (T1DM) patients, the expression of CD40 system components, as well as to explore the association of plasma and urine concentrations of CD40 with known inflammatory markers in T1DM. METHODS: Plasma, urine and peripheral blood mononuclear cells (PBMCs) from 70 T1DM patients without clinically detected chronic complications and 40 healthy controls (HCs) were examined using ELISA, western-blot, semi-quantitative RT-PCR and DNA-sequencing. RESULTS: Patients had significantly higher plasma soluble CD40 (sCD40) levels associated with higher Interleukin-6 (IL-6), matrix metalloproteinase-9 (MMP-9) and CRP levels compared with healthy controls. This difference was also evident between poorly and well-controlled diabetic patients. The elevated plasma sCD40 levels do not appear to be due to diminished renal excretion since sCD40 concentrations in the urine were also elevated, suggesting an increased CD40 production. An upregulation of PBMCs' CD40 was evident in T1DM patients associated with higher sCD40, IL-6 and CRP levels. Furthermore, the main CD40 isoform (isoform-I) was solely expressed in poorly controlled diabetics' PBMCs, who also demonstrated cellular CD40 upregulation, higher plasma CD40, CRP, IL-6 and MMP-9 levels compared with the well-controlled diabetics and the control group, who co-expressed type I and II isoforms. CONCLUSIONS: Homeostatic dysregulation of CD40 and its association with inflammatory markers in T1DM patients, especially in those with poor glycaemic control, implies a pathophysiological role of CD40 in the low-grade inflammatory process in T1DM.

The acute effect of Orlistat on dietary glycotoxins in diabetics and healthy women.

AIM: Advanced glycation end products (AGEs) formation is implicated in diabetic complications. Exogenous AGEs, namely glycotoxins, are present in certain foods and are absorbed from the gastrointestinal tract. Experimental data suggest that lifestyle interventions reducing their content in diet have beneficial effect. METHODS: Fourteen healthy (age: 42.14 +/- 12.38 years; body mass index [BMI]: 27.85 +/- 7.06 kg/m2) and ten women with type 2 diabetes (T2DM) (age: 48.70 +/- 9.31 years; BMI: 32.55 +/- 7.14 kg/m2) were enrolled in the study. A meal rich in AGEs was provided in a two-day protocol and on day 2, 240 mg of Orlistat were administered post-meal. RESULTS: On day 1, serum AGEs levels showed a rise at 3 hours post-meal compared to baseline values in both groups (controls: 12.2%; P<0.001), T2DM: 2.6%; P=0.013), but at 5 hours post-meal only in the controls (control: 12.2%; P<0.001); T2DM: 1.9%; P=0.075). On day 2 at 3 hours post-meal control values showed a rise of 3.1% (P=0.003); T2DM of 1.9% (P=0.013); at 5 hours post-meal rise for controls was 4.6% (P=0.012); and for T2DM was 1.8% (P=0.009). The corresponding rise was significantly lower on day 2 only in controls at 3 and 5 hours post-meal (P=0.003; P=0.05, respectively). CONCLUSIONS: Orlistat reduced the absorption of glycotoxins acutely and improved the metabolic profile in the control group, without an apparent beneficial effect in the diabetic group. The clinical significance of this observation should be further investigated in normal population, while in diabetics long-term studies may be required to demonstrate possible clinically significant effects.

The effect of pharmaceutical intervention on lipid profile in polycystic ovary syndrome.

The polycystic ovary syndrome (PCOS), a prevalent endocrinopathy of women, has been associated with a clustering of adverse metabolic features, which co-exist with reproductive dysfunction. Lipid abnormalities are very common in lean as well as obese women with PCOS and should be cautiously considered in the therapeutic management of the syndrome. Clinicians should also critically assess the lipidemic effect of pharmaceutical intervention, primarily aimed at hyperandrogenism, anovulation or insulin resistance. Because dyslipidemia may contribute to long-term cardiometabolic and reproductive sequelae in PCOS, it should be considered as an additional therapeutic target when these patients are assigned to appropriate pharmaceutical treatment.

Pancreatic beta-cells dysfunction in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a major risk factor for impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2D). Several studies have examined possible mechanisms related to glucose metabolism and insulin secretion that may be responsible for the high prevalence of disorders of glucose metabolism in women with PCOS. The actual pathogenic mechanisms appear to be complex and multifactorial, possibly characterized by the lack of uniformity between patients, thus reflecting the heterogeneity of PCOS. Impaired insulin action and/or beta-cell dysfunction and/or decreased hepatic clearance of insulin have been implicated so far. This article focuses on the role of beta-cell function in the increased predisposition to GDM and T2D in PCOS and the possible genetic basis of defects in insulin secretion. Conditions, like pregnancy and exogenous glucocorticoid administration, aggravate insulin resistance ,thereby placing additional strains upon beta-cells, which may be inherently prone to dysfunction in women with PCOS. The aggravation of insulin resistance amplifies the demands for insulin secretion by beta-cells. The resultant unfavourable state unmasks potential latent defects of beta-cell function, thereby possibly precipitating the development of T2D or of gestational diabetes (GDM) in pregnant women with PCOS. In addition to metabolic sequelae, insulin resistance and compensatory hyperinsulinemia contribute to ovarian dysfunction,manifested by hyperandrogenemia and anovulation, characterizing PCOS. The role of ovarian androgen excess in metabolic aberrations,specifically insulin action and secretion remains unclears.