Przeprowadzona z wykorzystaniem zależnej od ligacji multipleksowej amplifikacji sond analiza genów KAL1, GNRH1, GNRHR, PROK2 i PROKR2 u pacjentów płci męskiej z idiopatycznym hipogonadyzmem hipogonadotropowym

Introduction: The purpose of this study was to determine the prevalence of KAL1, GNRH1, GNRHR, PROK2, and PROKR2 copy numbervariations in patients with idiopathic hypogonadotropic hypogonadism (IHH).Material and methods: 86 hypogonadal males (76 diagnosed with normosmic idiopathic hypogonadotropic hypogonadism [nIHH] andten with Kallmann syndrome [KS]) and 95 healthy control individuals were studied for the presence of aforementioned genomic rearrangements,using multiplex ligation dependent probe amplification (MLPA).Results: We detected that of the 86 patients, three with KS had a deletion of the KAL1 gene in exon 9, one of whom also carried a duplicationin exon 11; and three with nIHH had a duplication of the PROK2 gene in exon 3; a deletion of the GNRHR gene in exon 1; anda duplication of the same gene in exon 2, respectively. No abnormalities were found in the patient group for the PROKR2 and GNRH1genes. In addition, no genomic rearrangements were identified in the healthy control individuals for the described genes.Conclusions: Defining the genetic basis of disease is essential to improve our understanding of this complex disorder, and could be usefulfor genetic counselling and for directing therapy. In addition, discovering the association between genetic mutations and disease isimportant for our better understanding of normal reproductive functions.Wstęp: Celem badania było ustalenie rozpowszechnienia zmienności liczby kopii genów KAL1, GNRH1, GNRHR, PROK2 i PROKR2u pacjentów z idiopatycznym hipogonadyzmem hipogonadotropowym (IHH, idiopathic hypogonadotropic hypogonadism).Materiał i metody: Obecność wymienionych wyżej rearanżacji genomowych zbadano metodą zależnej od ligacji multipleksowej amplifikacjisond (MLPA, multiplex ligation dependent probe amplification) u 86 mężczyzn z hipogonadyzmem — w tym u 76 z rozpoznaniemIHH przebiegającego bez zaburzeń węchu (nIHH, normosmic idiopathic hypogonadotropic hypogonadism) i u 10 z rozpoznaniem zespołuKallmanna (KS, Kallmann syndrome) — oraz u 95 zdrowych osobników kontrolnych.Wyniki: U 3 pacjentów z KS stwierdzono delecję w obrębie genu KAL1 w egzonie 9, przy czym u jednego z nich występowała też duplikacjaw egzonie 11. Z kolei łącznie u 3 pacjentów z nIHH stwierdzono: duplikację w obrębie genu PROK2 w egzonie 3 u jednego pacjenta,delecję w obrębie genu GNRHR w egzonie 1 u drugiego pacjenta oraz duplikację obrębie tego samego genu w egzonie 2. Jeśli zaś chodzi ogeny PROKR2 i GNRH1, to w grupie pacjentów nie stwierdzono żadnych nieprawidłowości w tym zakresie. Nie stwierdzono też żadnychrearanżacji genomowych w zakresie wymienionych genów u zdrowych osobników kontrolnych.Wnioski: Określanie podłoża genetycznego ma ogromne znaczenie dla pogłębiania wiedzy na temat tej złożonej choroby i możebyć przydatne w poradnictwie genetycznym i ustalaniu leczenia. Ponadto odkrywanie powiązań pomiędzy mutacjami genetycznymia omawianą chorobą ma duże znaczenie dla pogłębiania wiedzy na temat prawidłowego funkcjonowania układu rozrodczego

Wpływ testosteronowej terapii zastępczej na stężenia witaminy D i FGF-23 w hipogonadyzmie wrodzonym

Introduction: Patients with hypogonadism are at increased risk of cardiac and metabolic diseases and osteoporosis. Vitamin D and Fibroblast growth factor-23 (FGF-23) play role in the regulation of bone mineral metabolism and endothelial functions. Low vitamin D levels are reported in hypogonadism, while there is no data about the effect of testosterone replacement therapy (TRT). We investigated the effect of TRT on vitamin D and FGF-23 levels along with endothelial functions and insulin resistance in hypogonadal patients. Material and methods: Patients with congenital hypogonadotrophic hypogonadism (CHH) (n=32, age 20.6 ±1.58 years) were enrolled. TRT was implemented in transdermal form. The demographic parameters, FGF-23, 25(OH)D3, Asymmetric dimethylarginine (ADMA) and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured both before and after TRT. Results: After a follow-up period of 3.63±1.33 months, ADMA and FGF-23 levels were significantly increased (p=0.03 and p=0.005 respectively), while the 25(OH)D3 and HOMA-IR index were not significantly changed. The body mass index and waist circumference levels of the patients were also increased (p<0.001 and p=0.02) along with a significant decrease in the HDL cholesterol levels (p=0.006). Conclusions: The results show that a short term TRT increases plasma FGF-23 and ADMA levels, in young, treatment naive patients with CHH. Whether this is an early implication of TRT related adverse effects in this very young and treatment naïve population of CHH is not clear. Future prospective studies are required to find out the long-term effects of TRT on cardio-metabolic morbidity and mortality in this specific population.  Wstęp: U chorych z hipogonadyzmem występuje zwiększone ryzyko chorób sercowych I metabolicznych oraz osteoporozy. Witamina D i czynnik wzrostu fibroblastów-23 (FGF-23) uczestniczą w regulacji metabolizmu kostnego i czynności śródbłonka. Istnieją doniesienia na temat niskiego stężenia witaminy D w hipogonadyzmie, natomiast brakuje danych dotyczących wpływu testosteronowej terapii zastępczej (TRT) na to stężenie. Autorzy zbadali wpływ TRT na stężenia witaminy D i FGF-23 oraz na czynność śródbłonka i poziom insulinooporności u chorych z hipogonadyzmem. Materiał i metody: Do badania włączono chorych z wrodzonym hipogonadyzmem hipogonadotropowym (CHH) (n = 32, wiek 20,6 ± 1,58 roku). Chorzy otrzymywali TRT w postaci przezskórnej. Przez rozpoczęciem leczenia i po jego zakończeniu u chorych zebrano dane demograficzne, zmierzono stężenia FGF-23, 25(OH)D3 i asymetryczej dimetyloargininy (ADMA) oraz określono wskaźnik insulinooporności HOMA-IR. Wyniki: Po okresie obserwacji trwającym 3,63 ± 1,33 miesiąca stwierdzono istotne zwiększenie stężeń ADMA i FGF-23 (odpowiednio p = 0,03 i p = 0,005), natomiast stężenie 25(OH)D3 i wskaźnik HOMA-IR nie zmieniły się istotnie. Ponadto zaobserwowano u chorych zwiększenie wskaźnika masy ciała i obwodu pasa (p < 0,001 I p = 0,02) oraz istotne zmniejszenie stężenia cholesterol frakcji HDL (p = 0,006). Wnioski: Wyniki badania pokazują, że krótkotrwałe stosowanie TRT u młodych chorych z CHH, uprzednio nieleczonych, powoduje zwiększenie osoczowego stężenia FGF-23 i ADMA, lecz nie wpływa na stężenie witaminy D. Nie jest jasne, czy jest to wczesny efekt działań niepożądanych TRT w tej grupie bardzo młodych pacjentów z CHH. Konieczne są dalsze prospektywne badania w celu ustalenia długookresowego wpływu TRT na chorobowość i śmiertelność w związku z chorobami sercowymi i metabolicznymi w tej szczególnej populacji

Endothelial dysfunction and insulin resistance in young women with polycystic ovarian syndrome

Background/aim: To evaluate whether there is a correlation between insulin resistance and nitric oxide-related endothelial dysfunction in patients with polycystic ovarian syndrome (PCOS). Materials and methods: The study was conducted with 25 young women with PCOS and 25 young healthy women, between 18 and 35 years of age. Plasma asymmetric dimethylarginine (ADMA) levels, serum nitric oxide (NO) levels, and homeostatic model assessment of insulin resistance (HOMA-IR) rates were measured in both the patient and control groups. Results: Plasma ADMA levels were significantly higher in PCOS patients than in the controls (P = 0.001). Serum NO levels were significantly lower in patients than in the controls (P = 0.008). The HOMA-IR rates, accepted as an insulin resistance parameter, were significantly higher in patients than in the controls (P = 0.001). Conclusion: Results of the present study indicate that, independent of age, body mass index, and blood lipid profile, there is significant insulin resistance in PCOS patients. However, no correlation was found between HOMA-IR as an insulin resistance determinant and altered ADMA and NO levels. This finding may indicate that there are additional mechanisms of cardiovascular risks in PCOS patients other than insulin resistance

Relationship between hemoglobin and CD40 ligand in prediabetes

Purpose: Hemoglobin (Hb) regulates the endothelial function by modulating the bio-availability of NO at the tissue level. A significant direct relationship is present between the Hb levels and endothelial functions in patients with Type 2 diabetes. Testing whether this association also exists in subjects with prediabetes is important because prediabetes is associated with an increased risk of cardiovascular disease and mortality. Therefore, we investigated the association of Hb both with the classical cardiac risk factors and the markers for endothelial dysfunction and inflammation, in subjects with impaired glucose tolerance (IGT). Methods: We enrolled 69 normotensive, and cardiovascular events free subjects with IGT (M=40, age=45.50±6.8 yr). Plasma insulin, hsCRP, soluble CD40L, vonWillebrand factor, p-selectin levels were measured. The parameters given according to the higher and lower median Hb values of the subjects were compared. Results: Subjects with the higher Hb levels exhibited lower HDL-C (46.68±10.8 mg/dl vs 51.5±8.9mg/dl; P=0.04) and higher systolic (122.57±6.2mmHg vs 116.17±7.4mmHg; p < 0.001) and diastolic (79.14±3.73mmHg vs 75.58±6.1mmHg; P=0.005) blood pressures and sCD40L (7.9±3.8ng/ml vs 6.07±2.1 ng/ml; P=0.02) levels. Hb levels were correlated to the HDL cholesterol, sCD40L, systolic and diastolic blood pressures and waist circumference (r=-0.28, P=0.02; r=0.29, P=0.02; r=0.53, P < 0.001; r=0.41, P=0.001; r=0.42, P < 0.001 respectively). According to the multiple logistic regression analysis, Hb was the determinant of sCD40L levels (?=0.437, P < 0.001). Conclusion: These results indicate that there may be a link with higher Hb values and cardiovascular risk factors in patients with IGT. Further investigation is warranted to understand the clinical implications of these findings in subjects with prediabetes

Visceral adiposity index and triglyceride/high-density lipoprotein cholesterol ratio in hypogonadism

ABSTRACT Background Cardiometabolic risk is high in patients with hypogonadism. Visceral adiposity index (VAI) and triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio are the practical markers of atherosclerosis and insulin resistance and independent predictors of cardiaovascular risk. To date, no study has evaluated VAI levels and TG/HDL-C ratio in hypogonadism. Subjects and methods A total of 112 patients with congenital hypogonadotrophic hypogonadism (CHH) (mean age, 21.7 ± 2.06 years) and 124 healthy subjects (mean age, 21.5 ± 1.27 years) were enrolled. The demographic parameters, VAI, TG/HDL-C ratio, asymmetric dimethylarginine (ADMA), high-sensitivity C-reactive protein (hs-CRP), and homeostatic model assessment of insulin resistance (HOMA-IR) levels were measured for all participants. Results The patients had higher total cholesterol (p = 0.04), waist circumference, triglycerides, insulin, and HOMA-IR levels (p = 0.001 for all) than the healthy subjects. VAI and ADMA and TG/HDL-C levels were also higher in patients than in healthy subjects (p < 0.001 for all). VAI was weakly correlated with ADMA (r = 0.27, p = 0.015), HOMA-IR (r = 0.22, p = 0.006), hs-CRP (r = 0.19, p = 0.04), and total testosterone (r = −0.21, p = 0.009) levels, whereas TG/HDL-C ratio was weakly correlated weakly with ADMA (r = 0.30, p = 0.003), HOMA-IR (r = 0.22, p = 0.006), and total testosterone (r = −0.16, p = 0.03) levels. Neither VAI nor TG/HDL-C ratio determined ADMA, HOMA-IR, and hs-CRP levels. Conclusions The results of this study demonstrate that patients with hypogonadism have elevated VAI and TG/HDL-C ratio. These values are significantly correlated with the surrogate markers of endothelial dysfunction, inflammation, and insulin resistance. However, the predictive roles of VAI and TG/HDL-C ratio are not significant. Prospective follow-up studies are warranted to clarify the role of VAI and TG/HDL-C ratio in predicting cardiometabolic risk in patients with hypogonadism