Male hypogonadism: an extended classification based on a developmental, endocrine physiology-based approach.

Normal testicular physiology results from the integrated function of the tubular and interstitial compartments. Serum markers of interstitial tissue function are testosterone and insulin-like factor 3 (INSL3), whereas tubular function can be assessed by sperm count, morphology and motility, and serum anti-Müllerian hormone (AMH) and inhibin B. The classical definition of male hypogonadism refers to testicular failure associated with androgen deficiency, without considering potential deficiencies in germ and Sertoli cells. Furthermore, the classical definition does not consider the fact that low basal serum testosterone cannot be equated to hypogonadism in childhood, because Leydig cells are normally quiescent. A broader clinical definition of hypogonadism that could be applied to male patients in different periods of life requires a comprehensive consideration of the physiology of the hypothalamic-pituitary-testicular axis and its disturbances along development. Here we propose an extended classification of male hypogonadism based on the pathophysiology of the hypothalamic-pituitary-testicular axis in different periods of life. The clinical and biochemical features of male hypogonadism vary according to the following: (i) the level of the hypothalamic-pituitary-testicular axis primarily affected: central, primary or combined; (ii) the testicular cell population initially impaired: whole testis dysfunction or dissociated testicular dysfunction, and: (iii) the period of life when the gonadal function begins to fail: foetal-onset or postnatal-onset. The evaluation of basal testicular function in infancy and childhood relies mainly on the assessment of Sertoli cell markers (AMH and inhibin B). Hypergonadotropism should not be considered a sine qua non condition for the diagnosis of primary hypogonadism in childhood. Finally, the lack of elevation of gonadotropins in adolescents or adults with primary gonadal failure is indicative of a combined hypogonadism involving the gonads and the hypothalamic-pituitary axis.

Tumor necrosis factor alpha in ulcerative colitis and diverticular disease associated colitis.

Conventional treatment of moderate-severe ulcerative colitis (UC) has resulted in only a limited therapeutic benefit. Advancing knowledge of UC pathogenesis and recent advances in biotechnology have led to the development of biological agents that selectively target individual inflammatory pathways. In particular, the role of tumor necrosis factor alpha (TNF-alpha) in UC pathogenesis has been clarified by serological and immunohistochemical studies in humans and by experimental models. Clinical efficacy of anti-TNF-alpha therapy with infliximab has been assessed in two large controlled trials, showing a good compromise between therapeutic gain and safety. The aim of this review is to provide an insight into the role of TNF-alpha and anti-TNF-alpha therapy in patients with UC and diverticular disease associated colitis.

Antibiotic treatment strategies for Helicobacter pylori infection.

In the third decade of the Helicobacter pylori era several informations are available on its pathogenetic mechanisms, as well as on therapeutic approaches. A 7-14 day triple or quadruple regimens (proton pump inhibitor together with 2 antibiotics) are currently suggested as first-line treatment, but the success rate following these therapy is constantly decreasing worldwide. Therefore, new drugs are needed to treat such a widespread infection. Several patents of new antibiotics have been claimed in the last 5 years, and some of them showed a very powerful antibacterial activity in vitro, even against clarithromycin and metronidazole resistant strains. Among the new compounds, thienylthiazole derivatives, benzamide derivatives and pyloricidins should be regarded as very promising molecules.

An unusual endoscopic finding: Trichuris trichiura. Case report and review of the literature.

Detection of Trichuris trichiura during colonoscopic examination is an unusual finding, at least in developed countries. We report a case of a coincidental endoscopic diagnosis of whipworm infestation performed in a patient referred to our open-access endoscopy even before a faecal examination for ova and/or parasites had been performed. Review of literature on colonoscopic diagnosis of T. trichuria is provided.

High eradication rates of Helicobacter pylori with a new sequential treatment.

BACKGROUND: Eradication rates of Helicobacter pylori with standard triple therapy are disappointing, and studies from several countries confirm this poor performance. AIM: To assess the eradication rate of a new sequential treatment regimen compared with conventional triple therapy for the eradication of H. pylori infection. METHODS: One thousand and forty-nine dyspeptic patients were studied prospectively. H. pylori-infected patients were randomized to receive 10-day sequential therapy [rabeprazole (40 mg daily) plus amoxicillin (1 g twice daily) for the first 5 days, followed by rabeprazole (20 mg), clarithromycin (500 mg) and tinidazole (500 mg) twice daily for the remaining 5 days] or standard 7-day therapy [corrected] [rabeprazole (20 mg), clarithromycin (500 mg) and amoxicillin (1 g) twice daily]. H. pylori status was assessed by histology, rapid urease test and 13C-urea breath test at baseline and 6 weeks or more after completion of treatment. RESULTS: Higher eradication rates were found with the sequential regimen compared to the standard regimen (intention-to-treat: 92% vs. 74%, P < 0.0001; per protocol: 95% vs. 77%, P < 0.0001). Higher eradication rates were also seen in patients with peptic ulcer disease and non-ulcer dyspepsia. In both treatments, compliance was similar (> 90%), as was the rate of side-effects, which were mild. CONCLUSIONS: This 10-day sequential treatment regimen achieves high eradication rates in peptic ulcer disease and non-ulcer dyspepsia.

Decreased sympathetic inhibition in gastroesophageal reflux disease.

This study was undertaken to evaluate autonomic nervous system function in patients with gastroesophageal reflux disease. Based on clinical criteria, 28 consecutive patients with no history of heart, metabolic, or neurologic disease (mean age 41 y, range 20-62 y) reporting with upper gastrointestinal symptoms typical of gastroesophageal reflux underwent esophageal manometry, ambulatory 24-hour pH study with electrocardiographic monitoring, power spectral analysis of heart rate variability, and cardiovascular tests. Twelve healthy subjects served as controls. A positive result of prolonged esophageal pH study (pH in the distal esophagus less than 4, lasting more than 4.2% of recording time) was observed in 21 patients (reflux group); seven patients were categorized in the nonreflux group. No patient showed arrhythmias or any correlation between heart rate variability changes during electrocardiographic monitoring and episodes of reflux (pH less than 4, lasting more than 5 minutes). A decrease of sympathetic function occurred only in the reflux group (p <0.05) supported by the lower increase of systolic/diastolic blood pressure at sustained handgrip. No other cardiovascular tests showed statistically significant differences in the control or nonreflux groups. Total time reflux showed an inverse correlation with sympathetic function in the reflux group (r = -0.415, p <0.028). We concluded that there is some evidence for a slightly decreased sympathetic function in patients with gastroesophageal reflux disease that is inversely correlated with total time reflux. In these patients, decreased sympathetic function may cause dysfunction of intrinsic inhibitory control with increased transient spontaneous lower-esophageal sphincter relaxations, thus resulting in gastroesophageal reflux disease.

A triple therapy regimen after failed Helicobacter pylori treatments.

BACKGROUND: Following standard triple therapy, up to 20% of patients require further Helicobacter pylori eradication treatment. Data regarding the efficacy of re-treatment in these patients are scarce. AIM: To evaluate the efficacy of a triple therapy after one or more consecutive treatment failures. METHODS: A total of 51 patients with persistent H. pylori infection after at least one unsuccessful standard 1-week regimen were enrolled in the study. H. pylori infection at entry was assessed by rapid urease test and histology on biopsies from the antrum and the corpus. Patients were given a 2-week triple therapy, comprising ranitidine bismuth citrate 400 mg b.d., tetracycline 500 mg t.d.s., and tinidazole 500 mg b.d. Ranitidine bismuth citrate was given during meals, whilst tetracycline and tinidazole was given after meals. Bacterial eradication was assessed by endoscopy (36 patients) or 13C-urea breath test (15 patients) 4-6 weeks after therapy had ended. RESULTS: All 51 patients completed the study and H. pylori eradication was achieved in 46, with an eradication rate of 90% (95% CI: 82-98). In detail, bacterial eradication was obtained in 96% of patients who had previously failed one course of clarithromycin-amoxicillin based triple therapy, in 88% patients who had failed a clarithromycin-tinidazole based triple therapy, in 83% patients who had failed both treatment schedules, and in the only patient who had failed three consecutive therapeutic attempts. Two patients took the therapy for 9 and 10 days instead of the full 14 day-course. No major side-effects were reported, whilst six (12%) patients complained of mild side-effects. CONCLUSION: This study demonstrates that this triple therapy regimen is effective for re-treatment of H. pylori infection.

Acute pancreatitis with Purtscher's retinopathy: case report and review of the literature.

The case is described of a 32-year-old man suffering from alcoholism who came to the Emergency Unit with vomiting, fever and sharp epigastric pain irradiating to the chest and upper abdomen. A diagnosis of acute pancreatitis was made after high amylase and lipase levels were observed and the results of computed tomography scan revealed images typical of acute pancreatitis. Findings upon admission and after the initial 48 hours did not correlate with a severe or complicated course according to Ranson's criteria. On the third day after admission he suddenly developed decreased vision. A fluorescein angiogram showed arteriolar occlusion, retinal and choriocapillary ischaemia. Purtscher's retinopathy was suspected. After 4 weeks, the patient had recovered from acute pancreatitis, ophthalmoscopic examination showed normal results, and visual acuity had almost returned to normal. Activation of complement in acute pancreatitis could account for many haematologic acute disorders due to leucocyte emboli or other complement-mediated aggregates. Coagulation abnormalities may range from isolated intravascular thrombosis to severe disseminated intravascular coagulation. Purtscher's retinopathy, due to microembolizations in the choroidal and retinal arterioles, should be included among the various systemic effects of acute pancreatitis. This visual disorder is a rare systemic manifestation of acute pancreatitis which was not correlated to a severe or complicated clinical course. Treatment of these ocular complications remains to be established and outcome, therefore, depends upon resolution of the pancreatic disease.

Is infancy a quiescent period of testicular development? Histological, morphometric, and functional study of the seminiferous tubules of the cebus monkey from birth to the end of puberty.

The objective of this study was to describe the maturational changes observed in the seminiferous tubules of the monkey Cebus apella, a New World primate species, from birth to the end of puberty. Nineteen animals were subdivided into four groups: neonatal (1-40 days), infantile (4 months to 1 yr), early pubertal (1 yr, 8 months to 2 yr, 9 months), and late pubertal (4-8 yr). Volumetric determinations of different testicular components were made, tubule diameter and length were calculated, and spermatogenic cells, Sertoli cells, and androgen-binding protein secretion were quantified. Testicular and seminiferous tubule volumes increased significantly in the first 5 months of life and during puberty due to the combined increment in seminiferous tubule diameter and length. The total number of spermatogonia increased until late puberty to stabilize subsequently. Spermatocytes and spermatids appeared during puberty and increased dramatically until the end of this period. The germ cell ratios, indicative of spermatogenic efficiency, improved continuously in late puberty coincidentally with a reduction of spermatocyte degeneration. Sertoli cells proliferated in the neonatal and infantile periods, determining a longitudinal growth of the seminiferous tubules, but remained stable during puberty, when androgen-binding protein secretion increased significantly. The multiplication of germ cells is the main factor responsible for the increment in tubule diameter during puberty and determines the most noticeable postnatal modification of testicular volume. During late puberty, the reduction of spermatocyte degeneration leads to an increment in germ cell ratios and a progressive, but slow, improvement of spermatogenic efficiency, explaining why pubertal development of the testis occurs over such a prolonged period in this primate. This is in contrast to what happens in most laboratory animals and suggests that the Cebus is a useful model for studies of human male puberty.

Sex-hormone-binding globulin in human follicular fluid and serum at the time of oocyte recovery.

Androgen binding activity, indistinguishable from sex-hormone-binding globulin (SHBG) in serum, has been identified in human follicular fluid by binding analyses (saturation and Scatchard analyses and binding specificity), immunoradiometric assay and Con-A Sepharose chromatography. Follicular fluid was obtained at the time of oocyte recovery from either individual follicles (range 2-7) from seven patients, or as a pool obtained from follicles of several patients who had received a Clomid-human menopausal gonadotrophin treatment to stimulate follicular growth as part of an in vitro fertilization program. Concentrations of SHBG in follicular fluid varied between individual follicles (750 +/- 202 fmol mg-1 protein; mean +/- s.d.; n = 14) and ranged above and below concentrations of SHBG in serum (948 +/- 171 fmol mg-1 protein; n = 5) taken 4 h before oocyte recovery and harvest of follicular fluid. There were strong correlations (r = 0.7-0.9) between the steroid and SHBG contents in individual follicular fluids of two patients. However, the concentration of SHBG in follicular fluid was generally 100-fold lower than that of oestradiol or progesterone, suggesting that SHBG may play some role other than determining the concentration of unbound steroid in the follicle.

Distribution of specific androgen binding sites within the ovine ovarian follicle.

Two specific androgen binding sites were characterized in the ovine follicle with [3H]DHT, [3H]T and [3H]R-1881 as ligands, different incubation times and a charcoal separation step: the first, with characteristics very similar to testicular ABP in terms of its capacity, affinity, association and dissociation rates and specificity for natural and synthetic androgens, was found in serum, follicular fluid and the 27000 X g particulate and cytosol fractions of granulosa cells; the second, classic androgen receptors, were found in the cytosol with high affinity and low capacity for the synthetic androgen R-1881 and a very slow steroid-protein rate of dissociation. Saturation analysis on purified nuclei showed only the presence of the androgen receptor binding R-1881 with capacity similar to cytosol receptor. Isolated follicles showed a direct correlation between the total concentrations of androgen ([3H]-[3H]R-1881) binding sites and the follicular diameter. The complex actions which androgens exert on granulosa cell function may be mediated by interactions in vivo between these extra- and intracellular specific androgen binding proteins.