Global thromboelastometry in patients receiving direct oral anticoagulants: the RO-DOA study

Journal of Thrombosis and Thrombolysis - Rapidly available tests might be useful to measure the anticoagulant effect of direct oral anticoagulants (DOAs) in emergency situations as bleedings,...     

Identification of immunoreactive gastrin-releasing peptide related substances in adult rat Leydig cells

Purified adult rat Leydig cells were found to produce gastrin-releasing peptide (GRP) by radioimmunoassay (RIA). Gel chromatography of the extracted material showed a single peak of GRP immunoreactivity. Further high pressure liquid chromatography (HPLC) analysis resolved the extract into two peaks that closely resembled the C-terminal fragment of GRP, GRP18-27 and GRP14-27. Immunohistochemical studies revealed specific staining for GRP in the Leydig cells of adult rat testis. These results demonstrate, by a number of independent criteria, that rat Leydig cells contain substances which behave like authentic GRP-like peptides. Since the peptides appear to be of local origin, a paracrine function within the rat testis is suggested.     

Role of seminal prostaglandins in male fertility. II. Effects of prostaglandin synthesis inhibition on spermatogenesis in man

The effect of prostaglandin biosynthesis inhibition has been studied in two groups of infertile oligozoospermic patients with high or normal-low seminal prostaglandin (PG) levels. PGE and 19-OH PGE were assayed by means of a gas chromatographic method and the most important seminal parameters (volume, concentration, motility and morphology of spermatozoa) were evaluated in basal conditions and at the end of indomethacin treatment, at a daily oral dose of 100 mg for thirty days. A drop in prostaglandin levels following indomethacin was observed in both groups of patients but only in the group with high concentrations of prostanoid derivates the prostaglandin inhibition was correlated with a significant improvement in sperm count and motility.     

Interleukin-12 production by leukemia-derived dendritic cells counteracts the inhibitory effect of leukemic microenvironment on T cells

OBJECTIVE: Acute myeloid leukemia (AML) cells are poorly immunogenic and inhibit T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen-presentation capacity than undifferentiated leukemic blasts, but may not be fully competent to stimulate T cells previously inhibited by leukemic cells. MATERIALS AND METHODS: AML-DCs were generated from AML cells and used to stimulate proliferation and cytokine production by T cells previously inhibited by AML cells. AML-DCs were also transfected with interleukin (IL)-12 gene by the nonviral method, nucleofection. RESULTS: Mature AML-DCs stimulated naive and, to a lesser extent, leukemic cell (LC)-cultured T cells more efficiently than their immature counterparts and their activity was mediated by IL-12. AML-DCs generated from CD14(-) AML samples (which represent 80% of total AML patients) were defective in IL-12 production and T-cell activation. Addition of exogenous IL-12 to LC-cultured T cells stimulated by CD14(-)-derived AML-DCs restored optimal interferon-gamma (IFN-gamma) production and Th1 skewing. IL-12 gene-nucleofected AML-DCs derived from CD14(-) cells produced significant amounts of IL-12, maintained leukemia-specific karyotype, DC-like phenotype, and function. When stimulated by IL-12-gene transduced CD14(-)-derived AML-DCs, LC-cultured T cells produced higher concentrations of IFN-gamma, thus maintaining a Th1 cytokine profile. CONCLUSION: IL-12 produced by AML-DCs plays a critical role in counteracting the inhibitory activity of LCs on T-cell function. IL-12 gene can be successfully expressed into AML-DCs defective in endogenous IL-12 production by using a novel nonviral method that does not modify their phenotypical, cytogenetic, and functional features. Genetically modified AML-DCs restore a near normal T-cell function.     

Second chronic phase before transplantation is crucial for improving survival of blastic phase chronic myeloid leukaemia

Because successful outcome after transplantation seems to depend in acute myeloid leukaemia (AML) and in chronic phase chronic myeloid leukaemia (CML) on disease status at the time of transplantation, we investigated whether FLAN (fludarabine, cytosine arabinoside, mitoxantrone) induction before allogeneic stem cell transplantation (allo-SCT) may be useful in blastic phase (BP)-CML. Twenty patients with BP-CML were studied: 10 patients received FLAN induction chemotherapy before proceeding to early allo-SCT, whereas 10 patients were submitted to bone marrow transplantation (BMT) without remission induction. Eight out of 10 (80%) patients achieved second chronic phase after one course of therapy with FLAN and seven patients (six in second chronic phase and one with partial response) were then submitted to allo-SCT. Of the six patients transplanted in the second chronic phase, all achieved molecular remission, four are still in second chronic phase, with intervals ranging from 10 to 54 months, whereas one patient died from infection having relapsed 14 months after SCT and one died of transplant-related complications in the second chronic phase. Mean durations of second chronic phase and survival after allo-SCT were both significantly longer than in the group of 10 BP-CML patients submitted to allo-SCT without FLAN remission induction treatment [22.4 (range 1-61) vs. 3.5 months (range 1-10) with FLAN and 22.7 (range 2-61) vs. 6.4 (range 1-16) months without FLAN]. We conclude that FLAN induction therapy followed by early allo-SCT appears to be effective in the treatment of BP-CML and could provide a curative possibility for BP-CML patients.     

Discriminatory value of the low-dose dexamethasone suppression test in establishing the diagnosis and differential diagnosis of Cushing's syndrome

Cushing's syndrome requires a screening test of high sensitivity, followed by biochemical evaluation of the source of the tumor when the cause is ACTH dependent. The high-dose dexamethasone suppression test is still in common use as an aid in differential diagnosis, although its value has been queried. We have routinely used the low-dose dexamethasone suppression test for many years in the diagnosis of Cushing's syndrome but noticed that patients with pituitary-dependent Cushing's syndrome or Cushing's disease, usually showed some degree of suppression of their serum cortisol, compared to those with the ectopic ACTH syndrome. We therefore analyzed retrospectively the serum cortisol responses during the low-dose dexamethasone suppression test and the high-dose dexamethasone suppression test in 245 patients with ACTH-dependent Cushing's syndrome and compared the diagnostic utility of each test either alone or in combination with a standard test using CRH. Evaluation of the serum cortisol response at 24 and 48 h during the low-dose dexamethasone suppression test correctly identified 98% of patients with ACTH-dependent Cushing's syndrome and distinguished between pituitary and ectopic causes with a sensitivity of 82% and a specificity of 79%. In the same patients, the serum cortisol response to the high-dose dexamethasone suppression test had a slightly higher sensitivity (91%) and specificity (80%). However, the combined criteria of a more than 30% suppression of serum cortisol during the low-dose dexamethasone suppression test and/or a more than 20% increase in the CRH test had a significantly higher sensitivity (97%) and specificity (94%) than either the high-dose dexamethasone or the CRH tests alone in the differential diagnosis of ACTH-dependent Cushing's syndrome. It produced equivalent information to that when high-dose and CRH test results were combined. We therefore conclude that in our patient series, the serum cortisol response during the low-dose dexamethasone suppression test is highly sensitive in diagnosing Cushing's syndrome and, combined with the results of the serum cortisol response to the CRH test, offered a safe and cost-effective test in the differential diagnosis of ACTH-dependent Cushing's syndrome. There does not appear to be any necessity for retaining the high-dose dexamethasone suppression test in this diagnostic work-up.     

Low serum bioactive luteinizing hormone in nonorganic male impotence: possible relationship with altered gonadotropin-releasing hormone pulsatility

We determined the biological activity of serum LH in 23 men, aged 25-50 yr, complaining of nonorganic impotence of at least 1-yr duration and 20 normal men. All of the impotent men had normal general physical examinations, penile Doppler tests, psychological tests, and peripheral nerve conduction. Serum PRL, FSH, LH, and thyroid hormone concentrations were normal as were the results of provocative tests of TSH, gonadotropin, and PRL secretion. The mean serum immunoreactive LH (I-LH) levels, measured in each impotent and normal man in three samples taken at 15-min intervals, were similar [7.2 +/- 0.5 (+/-SE) vs. 6.4 +/- 0.5 mIU/mL (IU/L)]. In contrast, the mean serum bioactive LH (B-LH) level was significantly lower in the impotent men than in the normal men [15.9 +/- 2.1 (+/-SE) vs. 33.0 +/- 2.8 mIU/mL (IU/L); P less than 0.05], as was the LH bio- to immunoactive (B/I) ratio (2.1 +/- 0.2 vs. 5.6 +/- 0.5; P less than 0.02). The mean serum testosterone level in the impotent men, although all individual values were within the range of normal for our laboratory [200-900 ng/100 mL (693-3120 nmol/L)], was 25% lower than that in the normal men [347 +/- 23 vs. 450 +/- 26 ng/100 mL; P less than 0.05 (1204 +/- 81 vs. 1560 +/- 91 nmol/L)]. In addition, a significant positive correlation was found between serum testosterone levels and LH B/I ratios in the impotent men (r = 0.45; P = 0.029). Pulsatile LH secretion, measured in six impotent and four normal men in blood samples collected every 15 min for 6 h, was similar in the two groups. The mean serum I-LH levels were similar [7.5 +/- 1.1 (+/-SE) vs. 5.1 +/- 1.0 mIU/mL (IU/L)], while the mean serum B-LH level as well as the LH B/I ratio was significantly lower in the impotent men throughout the observation period [11.4 +/- 2.0 (+/-SE) vs. 26.0 +/- 3.2 mIU/mL (IU/L) and 1.4 +/- 0.2 vs. 5.4 +/- 0.6; P less than 0.05 and P less than 0.02, respectively]. The B-LH pulse amplitude in the impotent men was reduced [mean peak LH, 8.6 +/- 0.3 vs. 25.3 +/- 4.0 mIU/mL (IU/L); P less than 0.05], while the LH pulse frequency was similar in the two groups. The median intrapulse LH B/I ratios were significantly higher than the median interpulse ratios in both impotent (P = 0.02) and normal men (P = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

Male hypogonadism

The hypothalamic–pituitary–gonadal (HPG) axis regulates the development, endocrine and reproductive function of the gonads throughout all phases of life. Male hypogonadism is defined an inadequate gonadal function, as manifested by deficiency in gametogenesis and/or secretion of gonadal hormones. In most cases, male hypogonadism is diagnosed through detailed history, physical examination and a few basic hormonal evaluations. In selected cases, however, additional tests are needed to define the aetiology and the extent of HPG axis dysfunction. These include semen analysis, pituitary imaging studies, genetic studies, bone densitometry, testicular ultrasonography, testicular biopsy and hormonal dynamic testing. The stimulation tests of the HPG are of particular importance in the differential diagnosis of congenital delayed puberty versus pre-pubertal hypogonadism in children. This review will focus on the methods, indications and limitations of endocrine testing in the characterisation and differential diagnosis of male hypogonadism at various ages. A practical hands-on guide on how to perform these tests is also provided.     

Multicenter study on the prevalence of sexual symptoms in male hypo- and hyperthyroid patients

CONTEXT: Thyroid hormones have a dramatic effect on human behavior. However, their role on sexual behavior and performance has seldom been investigated in men. OBJECTIVE: The objective of this study was to evaluate the prevalence of sexual dysfunctions in patients with hyper- and hypothyroidism and their resolution after normalization of thyroid hormone levels. DESIGN AND SETTING: We conducted a multicenter prospective study at endocrinology and andrology clinics in university hospitals. PATIENTS: The study included 48 adult men, 34 with hyperthyroidism and 14 with hypothyroidism. MAIN OUTCOME MEASURES: Subjects were screened for hypoactive sexual desire (HSD), erectile dysfunction (ED), premature ejaculation (PE), and delayed ejaculation (DE) on presentation and 8-16 wk after recovery from the thyroid hormone disorder. RESULTS: In hyperthyroid men, HSD, DE, PE, and ED prevalence was 17.6, 2.9, 50, and 14.7%, whereas in hypothyroid men, the prevalence of HSD, DE, and ED was 64.3% and of PE was 7.1%. After thyroid hormone normalization in hyperthyroid subjects, PE prevalence fell from 50 to 15%, whereas DE was improved in half of the treated hypothyroid men. Significant changes were found in the subdomains of the International Index of Erectile Function; ejaculation latency time doubled after treatment of hyperthyroidism (from 2.4 +/- 2.1 to 4.0 +/- 2.0 min), whereas for hypothyroid men it declined significantly, from 21.8 +/- 10.9 to 7.4 +/- 7.2 (P < 0.01 for both). TSH and thyroid hormone levels normalized rapidly after treatment, and changes in circulating sex steroids partially reflected the changes in SHBG levels. CONCLUSIONS: In summary, most patients with thyroid hormone disorders experience some sexual dysfunctions, which can be reversed by normalizing thyroid hormone levels. Despite the associated changes in sex hormone levels, the high prevalence of ejaculatory disorders and their prompt reversibility suggest a direct involvement of thyroid hormones in the physiology of ejaculation.