Influence of the change of the hypothalamo-pituitary-adrenal axis reactivity on the outcome in patients with systemic inflammatory response

Uvod: Sindrom sistemskog inflamatornog odgovora (SIRS) predstavlja inflamatorno stanje uzrokovano infekcijom ili sepsom i koje se širi na ceo organizam. SIRS se smatra delom „citokinske oluje“ i manifestuje se disregulacijom različiutih citokina. Ozbiljnost bolesti se najbolje prediktuje korišćenjem APACHE II skora (Acute Physiology and Chronic Health Evaluation II) dok se ishod kod pacijenta, odnosno organska disfunkcija ili insuficijencija prediktuje pomoću SOFA skora (Sequential Organ Failure Assessment). SIRS dovodi do značajnih promena u dinamici kortizola ukazujući na disocijaciju između adrenalnog korteksa i hipotalamo-hipofizne jedinice. Navedena promena se manifestuje visokim koncentracijama kortizola i ACTH odmah nakon početka SIRS-a. Međutim, nekoliko dana kasnije, ACTH se spušta do veoma niskih koncentracija dok koncentracije kortizola ostaju visoke. Navedeno se objašnjava direktnim efektom citokina, kao što je interleukin 6 (IL-6), na koru nadbubrega koji stimulišu oslobađanje glukokortikoida. Odgovor kortizola na stimulaciju sa ACTH predstavlja važan prediktor ishoda kod kritično bolesnih. Bolesnici sa neadekvatnim odgovorom kortizola na stimulaciju sa ACTH imaju visoku stopu mortaliteta. Stimulacija sa 250 μg ACTH se smatra zlatnim standardom u proceni adrenalne funkcije. Međutim, niskodozni test sa 1 μg ACTH (NDT) predstavlja senzitivniji test u detekciji specifičnih formi adrenalne insuficijencije kao što je hipotalamo-hipofizna disfunkcija. Upotreba NDT u kritično obolelih nije jasno definisana jer postoji mali broj podataka za formiranje jasne preporuke...Introduction: Systemic inflammatory response syndrome (SIRS) represens inflamatory condition caused bz infection or sepsis that spreads all over the body. SIRS is considered a part of the „cytokine storm“ and is manifested by dysregulation of different cytokines. The severity of the disease is best predicted using Acute Physiology and Chronic Health Evaluation II (APACHE II) score while the patient’s outcome, namely organ dysfunction/failure during Intensive Care Unit (ICU) monitoring is predicted using Sequential Organ Failure Assessment (SOFA) score. SIRS leads to significant changes in cortisol dynamics indicating on the disociation between adrenal cortex and the hypothalamo-pituitary unit. This is manifested by the very high concentrations of cortisol and ACTH immediatly after commencement of SIRS. However, a few days later ACTH falls to the very low concentration while the concentrations of cortisol remains high. This is explained by direct effect of cytokines, as it is interleukin 6 (IL-6), on the adrenal cortex that is simulating glucocorticoid realease. Cortisol response on the stimulation with ACTH was shown to be important predictor of the outcome in critically ill patients. Patients with inadequate cortisol response on stimulation with ACTH had high mortality rate. Stimulation with 250 μg of ACTH is considered to be gold standard test for the assessment of adrenal function. However, the low-dose (1 μg) test (LDT) represents a more sensitive test for detecting specific forms of adrenal insufficiency as it is hypothalamo-pituitary disfunction. The use of LDT in critically ill patients is not clearly defined as the data on LDT are limited and not sufficient for the clear recommendation..

Polimorfizm S-transferazy glutationowej (GST) może być wczesnym markerem w rozwoju zespołu policystycznych jajników (PCOS) — doświadczenia nieotyłych dorosłych pacjentów z cukrzycą insulinoniezależną

Introduction: It has been supposed that endocrine disturbances might be responsible for polycystic ovary syndrome (PCOS)-associated oxida­tive stress, with special emphasis on hyperandrogenism. Considering the potential relationship between hyperandrogenism and increased free radical production, parameters of oxidative stress were determined in non-obese normoinsulinemic adolescent girls newly diagnosed with PCOS. Materials and methods: Nitrotyrosine, thiol group concentrations, glutathione peroxidase, and superoxide dismutase activities were determined under fasting conditions and during oral glucose tolerance test (OGTT) in 35 PCOS patients and 17 controls. Insulin resistance was assessed by the homeostasis model (HOMA-IR), HOMA β, insulinogenic index (IGI), Matsuda insulin sensitivity index (ISI), and AUC for glucose. Glutathione S-transferases (GSTs) polymorphisms were determined by PCR. Results: Under fasting conditions, no significant difference of oxidative stress parameters was found between PCOS and controls. Acute hyperglycaemia during OGTT induced significant alteration in parameters of oxidative protein damage in PCOS patients. Alteration in nitrotyrosine concentrations correlated with testosterone, DHEAS, androstenediones, FAI, and LH, while changes in thiol groups cor­related with DHEAS. Significant inverse association was found between LH and ISI, as well as AUC glucose and thiol groups. PCOS girls, carriers of GSTM1-null genotype, had significantly lower testosterone in comparison to ones with GSTM1-active genotype. Conclusions: PCOS girls exhibited high free radical production together with unchanged antioxidant enzymatic capacity, independently from obesity and insulin resistance. Based on associations between oxidative stress parameters and testosterone, DHEAS, and androsten­edione, it can be suggested that increased free radical production, probably as a consequence of hyperandrogenaemia, is an early event in the development of PCOS

Gojaznost i reproduktivna funkcija žene - mehanizmi nastanka i terapijske implikacije

Gojaznost se danas smatra uzrokom nastanka kardiovaskularne bolesti, tipa 2 dijabetesa, osteoartritisa, maligniteta, ali i faktorom koji doprinosi nastanku reproduktivnih poremećaja i problema plodnosti. Postoji povećan relativni rizik za nastanak anovulatornog infertiliteta u žena sa izraženom gojaznošću i produženo vreme do koncepcije. U žena u reproduktivnom periodu gojaznost je povezana sa povećanim rizikom za nastanak hiperandrogenizma i anovulacije, kao što je slučaj u sindromu policističnih jajnika (PCOS) kao najčešćem hiperandrogenom poremećaju. Postoji veliki broj dokaza u prilog postojanja bliskog odnosa adipokina, gojaznosti, metaboličkog sindroma i reproduktivnih posledica. Redukcija težine za 5-10% dovodi do poboljšanja u kliničkim, metaboličkim i reproduktivnim karakteristikama, kao što je slučaj u žena sa PCOS. Primena insulinskih senzitajzera vodi sniženju hiperinsulinemije, insulinske rezistencije, uspostavljanju normalne menstrualne cikličnosti i ovulacije kod značajnog broja žena sa PCOS. Gojaznost može uticati na stimulaciju ovulacije njenim produžavanjem, povećanjem doze gonadotropina, incidence folikularne asinhronije i prekida stimulacije. Hirurško lečenje gojaznosti predstavlja alternativni vid terapije u slučaju kada ni promena načina života ni farmakoterapijske mere ne daju povoljne rezultate. Za sada ne postoji dovoljno dokaza u prilog preporuke da se barijatrijska hirurgija koristi u lečenju gojaznih žena sa PCOS.Projekat ministarstva br. 175032 i br. 4100

Gojaznost i reproduktivna funkcija žene - mehanizmi nastanka i terapijske implikacije

Gojaznost se danas smatra uzrokom nastanka kardiovaskularne bolesti, tipa 2 dijabetesa, osteoartritisa, maligniteta, ali i faktorom koji doprinosi nastanku reproduktivnih poremećaja i problema plodnosti. Postoji povećan relativni rizik za nastanak anovulatornog infertiliteta u žena sa izraženom gojaznošću i produženo vreme do koncepcije. U žena u reproduktivnom periodu gojaznost je povezana sa povećanim rizikom za nastanak hiperandrogenizma i anovulacije, kao što je slučaj u sindromu policističnih jajnika (PCOS) kao najčešćem hiperandrogenom poremećaju. Postoji veliki broj dokaza u prilog postojanja bliskog odnosa adipokina, gojaznosti, metaboličkog sindroma i reproduktivnih posledica. Redukcija težine za 5-10% dovodi do poboljšanja u kliničkim, metaboličkim i reproduktivnim karakteristikama, kao što je slučaj u žena sa PCOS. Primena insulinskih senzitajzera vodi sniženju hiperinsulinemije, insulinske rezistencije, uspostavljanju normalne menstrualne cikličnosti i ovulacije kod značajnog broja žena sa PCOS. Gojaznost može uticati na stimulaciju ovulacije njenim produžavanjem, povećanjem doze gonadotropina, incidence folikularne asinhronije i prekida stimulacije. Hirurško lečenje gojaznosti predstavlja alternativni vid terapije u slučaju kada ni promena načina života ni farmakoterapijske mere ne daju povoljne rezultate. Za sada ne postoji dovoljno dokaza u prilog preporuke da se barijatrijska hirurgija koristi u lečenju gojaznih žena sa PCOS.Projekat ministarstva br. 175032 i br. 4100

Overweight and Obesity in Polycystic Ovary Syndrome: Association with Inflammation, Oxidative Stress and Dyslipidemia

Objective: Polycystic ovary syndrome (PCOS) is associated with altered lipid profile and increased small, dense LDL particles (sdLDL). Considering that paraoxonase 1 (PON1) is an anti-oxidative enzyme located on high-density lipoprotein (HDL) particles, the aim of this study was to investigate the connection between oxidative stress (OS) and PON1 activity with lipoprotein subclasses in PCOS depending on obesity. Methods: In 115 PCOS patients lipoprotein subclasses distributions were determined by gradient gel electrophoresis. OS status was assessed by total oxidative status (TOS), advanced oxidation protein products (AOPP), malondialdehyde (MDA), prooxidant-Antioxidant balance (PAB), total antioxidant status (TAS) and superoxide dismutase (SOD) and PON1 activity. Results: Overweight/obese PCOS patients (n=55) had increased OS compared to normal weight patients (n=60). In addition, overweight/obese group had lower HDL size and higher proportion of HDL 3a subclasses (P<0.05). PAB was in negative correlation with HDL 2a (P<0.001), whereas MDA and SOD correlated positively with HDL 3 subclasses (P<0.05). Serum PON1 activity was positively associated with proportions of PON1 activity on HDL 2b (P<0.05) and 2a (P<0.01), but negatively with the proportion on HDL 3 particles (P<0.01). LDL B phenotype patients had increased TAS, SOD and PON1 activity on HDL 2b, but decreased PON1 activity on HDL 3 subclasses. Conclusion: OS is associated with altered lipoprotein subclasses distribution in PCOS patients. Obesity in PCOS affects the profile of HDL subclasses, reflected through the reduced proportion of PON1 activity on HDL 3 subclasses in the presence of sdLDL particles.Peer-reviewed manuscript: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/3974

Evaluation of a Summary Score for Dyslipidemia, Oxidative Stress and Inflammation (The Doi Score) in Women with Polycystic Ovary Syndrome and its Relationship with Obesity

Background: Polycystic ovary syndrome (PCOS) is a cardiornetabolic disorder whose features include dyslipidemia, increased oxidative stress (OS, oxy) and chronic inflammation. The aim of this study was to investigate the ability of a summary score for dyslipidemia, OS and inflammation (the DOI score) to discriminate PCOS patients from healthy individuals and to evaluate the effect of obesity on individual scores and the DOI score in patients. Methods: Lipid status parameters, OS status parameters (advanced oxidation protein products; total oxidative status; prooxidant-antioxidant balance; malondialdehyde; total protein sulphydryl groups and paraoxonase 1 activity) and CRP were measured in 114 patients and 50 controls using standardised assays. The DOI score was calculated as the sum of dyslipidemia, oxy and inflammation scores, determined as Z-score values for every subject in relation to the controls. Results: PCOS patients had significantly higher oxy-score compared to controls (P lt 0.001). In addition, the DOI score was significantly higher in PCOS patients (P lt 0.001) as the dyslipidemia (P lt 0.05) and inflammatory scores (P lt 0.001) were greater. According to ROC analysis, the oxy-score showed better diagnostic accuracy in discriminating PCOS patients compared to the DOI score (AUC>0.9, P lt 0.01). Furthermore, obesity affected the risk scores in patients, especially the DOI score (significantly higher DOI scores in such patients, P lt 0.001). Conclusion: PCOS patients had greater dyslipidemia, chronic inflammation and OS compared to controls and could be segregated using all four scores. Our data suggest that weight gain could be the common factor responsible for induction and propagation of dyslipidemia, OS and inflammation in PCOS patients

Influence of the change of the hypothalamo-pituitary-adrenal axis reactivity on the outcome in patients with systemic inflammatory response

Uvod: Sindrom sistemskog inflamatornog odgovora (SIRS) predstavlja inflamatorno stanje uzrokovano infekcijom ili sepsom i koje se širi na ceo organizam. SIRS se smatra delom „citokinske oluje“ i manifestuje se disregulacijom različiutih citokina. Ozbiljnost bolesti se najbolje prediktuje korišćenjem APACHE II skora (Acute Physiology and Chronic Health Evaluation II) dok se ishod kod pacijenta, odnosno organska disfunkcija ili insuficijencija prediktuje pomoću SOFA skora (Sequential Organ Failure Assessment). SIRS dovodi do značajnih promena u dinamici kortizola ukazujući na disocijaciju između adrenalnog korteksa i hipotalamo-hipofizne jedinice. Navedena promena se manifestuje visokim koncentracijama kortizola i ACTH odmah nakon početka SIRS-a. Međutim, nekoliko dana kasnije, ACTH se spušta do veoma niskih koncentracija dok koncentracije kortizola ostaju visoke. Navedeno se objašnjava direktnim efektom citokina, kao što je interleukin 6 (IL-6), na koru nadbubrega koji stimulišu oslobađanje glukokortikoida. Odgovor kortizola na stimulaciju sa ACTH predstavlja važan prediktor ishoda kod kritično bolesnih. Bolesnici sa neadekvatnim odgovorom kortizola na stimulaciju sa ACTH imaju visoku stopu mortaliteta. Stimulacija sa 250 μg ACTH se smatra zlatnim standardom u proceni adrenalne funkcije. Međutim, niskodozni test sa 1 μg ACTH (NDT) predstavlja senzitivniji test u detekciji specifičnih formi adrenalne insuficijencije kao što je hipotalamo-hipofizna disfunkcija. Upotreba NDT u kritično obolelih nije jasno definisana jer postoji mali broj podataka za formiranje jasne preporuke...Introduction: Systemic inflammatory response syndrome (SIRS) represens inflamatory condition caused bz infection or sepsis that spreads all over the body. SIRS is considered a part of the „cytokine storm“ and is manifested by dysregulation of different cytokines. The severity of the disease is best predicted using Acute Physiology and Chronic Health Evaluation II (APACHE II) score while the patient’s outcome, namely organ dysfunction/failure during Intensive Care Unit (ICU) monitoring is predicted using Sequential Organ Failure Assessment (SOFA) score. SIRS leads to significant changes in cortisol dynamics indicating on the disociation between adrenal cortex and the hypothalamo-pituitary unit. This is manifested by the very high concentrations of cortisol and ACTH immediatly after commencement of SIRS. However, a few days later ACTH falls to the very low concentration while the concentrations of cortisol remains high. This is explained by direct effect of cytokines, as it is interleukin 6 (IL-6), on the adrenal cortex that is simulating glucocorticoid realease. Cortisol response on the stimulation with ACTH was shown to be important predictor of the outcome in critically ill patients. Patients with inadequate cortisol response on stimulation with ACTH had high mortality rate. Stimulation with 250 μg of ACTH is considered to be gold standard test for the assessment of adrenal function. However, the low-dose (1 μg) test (LDT) represents a more sensitive test for detecting specific forms of adrenal insufficiency as it is hypothalamo-pituitary disfunction. The use of LDT in critically ill patients is not clearly defined as the data on LDT are limited and not sufficient for the clear recommendation..

Influence of the change of the hypothalamo-pituitary-adrenal axis reactivity on the outcome in patients with systemic inflammatory response

Uvod: Sindrom sistemskog inflamatornog odgovora (SIRS) predstavlja inflamatorno stanje uzrokovano infekcijom ili sepsom i koje se širi na ceo organizam. SIRS se smatra delom „citokinske oluje“ i manifestuje se disregulacijom različiutih citokina. Ozbiljnost bolesti se najbolje prediktuje korišćenjem APACHE II skora (Acute Physiology and Chronic Health Evaluation II) dok se ishod kod pacijenta, odnosno organska disfunkcija ili insuficijencija prediktuje pomoću SOFA skora (Sequential Organ Failure Assessment). SIRS dovodi do značajnih promena u dinamici kortizola ukazujući na disocijaciju između adrenalnog korteksa i hipotalamo-hipofizne jedinice. Navedena promena se manifestuje visokim koncentracijama kortizola i ACTH odmah nakon početka SIRS-a. Međutim, nekoliko dana kasnije, ACTH se spušta do veoma niskih koncentracija dok koncentracije kortizola ostaju visoke. Navedeno se objašnjava direktnim efektom citokina, kao što je interleukin 6 (IL-6), na koru nadbubrega koji stimulišu oslobađanje glukokortikoida. Odgovor kortizola na stimulaciju sa ACTH predstavlja važan prediktor ishoda kod kritično bolesnih. Bolesnici sa neadekvatnim odgovorom kortizola na stimulaciju sa ACTH imaju visoku stopu mortaliteta. Stimulacija sa 250 μg ACTH se smatra zlatnim standardom u proceni adrenalne funkcije. Međutim, niskodozni test sa 1 μg ACTH (NDT) predstavlja senzitivniji test u detekciji specifičnih formi adrenalne insuficijencije kao što je hipotalamo-hipofizna disfunkcija. Upotreba NDT u kritično obolelih nije jasno definisana jer postoji mali broj podataka za formiranje jasne preporuke...Introduction: Systemic inflammatory response syndrome (SIRS) represens inflamatory condition caused bz infection or sepsis that spreads all over the body. SIRS is considered a part of the „cytokine storm“ and is manifested by dysregulation of different cytokines. The severity of the disease is best predicted using Acute Physiology and Chronic Health Evaluation II (APACHE II) score while the patient’s outcome, namely organ dysfunction/failure during Intensive Care Unit (ICU) monitoring is predicted using Sequential Organ Failure Assessment (SOFA) score. SIRS leads to significant changes in cortisol dynamics indicating on the disociation between adrenal cortex and the hypothalamo-pituitary unit. This is manifested by the very high concentrations of cortisol and ACTH immediatly after commencement of SIRS. However, a few days later ACTH falls to the very low concentration while the concentrations of cortisol remains high. This is explained by direct effect of cytokines, as it is interleukin 6 (IL-6), on the adrenal cortex that is simulating glucocorticoid realease. Cortisol response on the stimulation with ACTH was shown to be important predictor of the outcome in critically ill patients. Patients with inadequate cortisol response on stimulation with ACTH had high mortality rate. Stimulation with 250 μg of ACTH is considered to be gold standard test for the assessment of adrenal function. However, the low-dose (1 μg) test (LDT) represents a more sensitive test for detecting specific forms of adrenal insufficiency as it is hypothalamo-pituitary disfunction. The use of LDT in critically ill patients is not clearly defined as the data on LDT are limited and not sufficient for the clear recommendation..

Frequency of other endocrine disorders in hypothyroidism

Hypothyroidism is a condition of reduced production, distribution, or absence of action of thyroid hormones. Clinical diagnosis of hypothyroidism is not easily established due to the nonspecific clinical manifestations. Determination of serum TSH is the first-line test for the diagnosis of hypothyroidism. The aim of the study was to determine the presence of other endocrine disorders in patients with subclinical (TSH levels between 5 and 10 mIU/l), or clinical (TSH above 10 mIU/l) hypothyrodism. We analyzed 50 patients (35 with clinical hypothyroidism and 15 with subclinical form). In all patients anthropometric data (age, sex, weight, height, body mass index, blood pressure and heart rate), and clinical signs of hypothyroidism (skin changes, menstrual disorders) were determined. Blood was drawn in fasting state for measurement of FT4, sTSH, glucose, lipids, ionized calcium, PTH, cortisol, ACTH, prolactin, gonadotropins, estradiol in women of reproductive age, and testosterone in men. Skin lesions were rarely present. Oligomenorrhea was more frequent in subclinical hypothyroidism, and menopause in clinical hypothyroidism. Blood pressure was normal in all subjects. Patients with clinical hypothyroidism compared to those with subclinical form had higher TSH values (19.5 ± 5.7 vs. 5.9 ± 0.3 mIU/l), and higher doses of L-thyroxine (81.2 ± 4.6 vs. 21.4 ± 3.5 μg/day). Disturbance of glycemic control was present in 18% of patients. Total cholesterol and LDL were insignificantly higher in patients with hypothyroidism than in subclinical form of the disease. FT4, calcium, PTH, cortisol, ACTH, gonadotropins, estradiol and testosterone did not differ between groups. The proatherogenic relation of estradiol with triglycerides was established in women with clinical form of hypothyroidism

Clinical significance of intramammary arterial calcifications in diabetic women

Background. It is well known that intramammary arterial calcifications diagnosed by mammography as a part of generalized diabetic macroangiopathy may be an indirect sign of diabetes mellitus. Hence, the aim of this study was to determine the incidence of intramammary arterial calcifications, the patient’s age when the calcifications occur, as well as to observe the influence of diabetic polineuropathy, type, and the duration of diabetes on the onset of calcifications, in comparison with nondiabetic women. Methods. Mammographic findings of 113 diabetic female patients (21 with type 1 diabetes and 92 with type 2), as well as of 208 nondiabetic women (the control group) were analyzed in the prospective study. The data about the type of diabetes, its duration, and polineuropathy were obtained using the questionnaire. Statistical differences were determined by Mann-Whitney test. Results. Intramammary arterial calcifications were identified in 33.3% of the women with type 1 diabetes, in 40.2% with type 2, and in 8.2% of the women from the control group, respectively. The differences comparing the women with type 1, as well as type 2 diabetes and the controls were statistically significant (p=0.0001). Women with intramammary arterial calcifications and type 1 diabetes were younger comparing to the control group (median age 52 years, comparing to 67 years of age, p=0.001), while there was no statistically significant difference in age between the women with calcifications and type 2 diabetes (61 years of age) in relation to the control group (p=0.176). The incidence of polineuropathy in diabetic women was higher in the group with intramammary arterial calcifications (52.3%) in comparison to the group without calcifications (26.1%), (p=0.005). The association between intramammary arterial calcifications and the duration of diabetes was not found. Conclusion. The obtained results supported the theory that intramammary arterial calcifications, detected by mammography could serve as markers of co-existing diabetes mellitus and therefore should be specified in radiologic report in case of their early development