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There has been a longstanding question as to whether testosterone therapy could precipitate or worsen urinary symptoms in aging men. We investigated the effects of 1-year oral testosterone undecanoate (TU) therapy on urinary symptoms in aging, hypogonadal men.A total of 322 men ≥50 years with symptomatic testosterone deficiency participated in a 1-year, randomized, multicenter, double-blind trial. Patients received placebo or oral TU 80 mg/day, 160 mg/day, or 240 mg/day.Compared with placebo, treatment with oral TU at doses of 80 mg/day and 160 mg/day resulted in no significant change in IPSS urinary symptoms or quality of life (QoL) scores. Treatment with oral TU 240 mg/day led to a statistically significant, but clinically insignificant, improvement in IPSS total score and a significant improvement in IPSS QoL score. None of the TU doses tested had a significant effect on PSA or PV.Long-term oral TU therapy had no deleterious effects on IPSS total score and did not change PV and PSA in aging, hypogonadal men. Oral TU therapy at a dose of 240 mg/day may even improve IPSS QoL score.

What's known on the subject? and What does the study add? Hypogonadism affects an estimated 2–4 million men in the USA, but only 5% receive treatment. Testosterone replacement therapy reduces the effects of testosterone deficiency on sexual function, mood and energy in hypogonadal patients. Long-term hypogonadism management requires testosterone treatment to restore serum concentrations of testosterone and its active metabolites, within physiological ranges; a testosterone preparation that achieves physiological plasma concentrations without supra-physiological escape is a preferred option. A previous 1-year study European clinical study showed the efficacy and safety of a transdermal testosterone patch (Testopatch®). The present study shows the long-term (6-year) safety and efficacy of Testopatch in patients with primary or secondary hypogonadism. We show that, over the long-term, Testopatch was associated with no relevant changes in PSA concentration and PSA velocity, or any significant prostate risks (there were no cases of prostate cancer). Objective To assess the change in prostate-specific antigen (PSA) concentrations in patients with primary or secondary hypogonadism, receiving transdermal testosterone. Patients and Methods This was an interventional, 6-year study, conducted in Urology and Endocrinology centres in Belgium, France, Germany, the Netherlands and Spain. Participants were primary (48%) or secondary (52%) hypogonadal patients who received two 60 cm2 testosterone patches (Testopatch®), delivering 4.8 mg of testosterone per day, applied every 2 days. During treatment, total testosterone (TT), dihydrotestosterone, oestradiol and, PSA concentrations were measured in a centralised laboratory every 3 months during the first year, and every 6 months thereafter. Results In all, 200 patients [mean (sd) age 41.0 (12.5) years, body weight 82.5 (13.7) kg, height 177.2 (9.3) cm, body mass index 26.2 (3.4) kg/m2] were treated with transdermal testosterone patches. In all, 161 patients completed the 1-year study and 115 entered into a 5-year study extension; 51 patients completed the sixth year of the study. The mean baseline concentrations of TT and PSA were 1.4 ng/mL and 0.47 ng/mL, respectively; TT serum concentrations >3 ng/mL were achieved in 85% of patients and fluctuated between 4.4 and 6.0 ng/mL. At each successive 6-month time point, mean the PSA values were 0.60, 0.67, 0.76, 0.70, 0.61, 0.68, 0.64, 0.71, 0.75, 0.74, 1.01, 0.78, 0.80 ng/mL, respectively. The mean PSA velocity was negligible (0.00–0.03 ng/mL/year) from 30 months to the end of the trial, except for a value of 0.08 at 60 months. Seven patients had a PSA concentration of >4 ng/mL due to a sharp PSA increase. Six of these patients had prostatitis and PSA concentrations returned to previous levels with appropriate treatment. No prostate cancer was reported during the trial. Conclusion These data support a strong safety profile for Testopatch, even at the highest registered dosage.

Division of Endocrinology, Department of Medicine, Harbor-UCLA Medical Center and Los Angeles BioMedical Research Institute, Torrance, CA, USA, Centre for Reproductive Medicine and Andrology, University of Muenster, Muenster, Germany, Center for Reproductive Medicine and Andrology, University Hospital Halle, Martin-Luther-University Halle-Wittenberg, Halle, Germany, Department of Urology, Tulane University, New Orleans, LA, USA, Department of Endocrinology, VU University Medical Center, Amsterdam, The Netherlands, Department of Endocrinology, Academish Ziekenhuis, Gent, Belgium, Centre Hospitalier Universitaire, Sart-Tilman, Liege, Belgium, Faculty of Life Science, Bar-Ilan University, Ramat-Gan, Israel, Centre for Applied Urological Research, Queen’s University, Kingston, Canada, Division of Geriatric Medicine, St. Louis University and GRECC, St. Louis VA Medical Center, St. Louis, MO, USA, Department of Urology, Erasme Hospital, University Clinics Brussels, Brussels, Belgium, Department of Urology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA, Department of Urology and Pediatric Urology, University Hospitals, Justus-Liebig-University, Giessen, Germany, and Department of Endocrinology, University of Manchester, Manchester Royal Infirmary, Manchester, UK

The purpose of the present study was to assess if AVP-neurophysin is associated with hypercortisolemia and suicidal behaviour in depressed patients. The study included 28 patients subgrouped into suicide attempters (n=13) and nonattempters (n=15). We assessed basal AVP-neurophysins concentrations and post-dexamethasone (DST) cortisol levels. Concentrations of AVP-neurophysins did not differ between DST suppressors and nonsuppressors: 0.29+/-0.13 ng/ml vs 0.36+/-0.21 ng/ml, (F=1.1, df=1, 27, p=0.30). Suicide attempters did not differ from nonattempters for AVP-neurophysins levels. Our results fail to support a role of AVP in the early cortisol escape. Language: en

Vasopressin (AVP) and oxytocin (OT) were the first biologically active peptides to be synthesized. They are two chemically very similar neurohypophyseal neuropeptides which could be involved in mood disorders. Neuropeptides, short-chain amino-acid neurotransmitters and neuromodulators, are attractive therapeutic targets for mood disorders. AVP seems to play an important role in the pathophysiology of major depression. There are both clinical and laboratory evidences suggest a role for OT as an endogenous antidepressant/anxiolytic hormone. OT release is also an important aspect of pharmacological action of SSRIs. In addition to AVP and OT, their receptors are growing off interest for psychiatric research. Vasopressin receptor antagonist might represent potential agents for the treatment of depression. A selective, nonpeptide AVP V1b receptor antagonist, SSR149415, has been characterized and is endowed with anxiolytic- and antidepressant-like properties. For the treatment of depression, Vasopressin antagonist and the related patents are also discussed in this article.

We observed oat-cell lung carcinoma in a man who presented with diabetes insipidus. The chest radiograph showed a suspect nodule within a context of major nicotine addiction. Histopathological examination of the transbronchial biopsy confirmed the diagnosis of oat-cell carcinoma. Brain CT revealed metastasis to the pituitary gland and the pituitary stalk. Vasopressin was undetectable. This case illustrates an uncommon clinical presentation of small-cell lung carcinoma. Oat-cell carcinoma can modify osmoregulation in two different ways. Only sporadic cases of neurogenic diabetes insipidus due to the primary involvement of small-cell lung carcinoma have been reported. More often, this type of lung tumor is associated with inappropriate antidiuretic hormone secretion.

The measurement of bioavailable testosterone (BT) or free testosterone (FT) levels is currently considered the gold standard for the diagnosis of androgen deficiency in elderly men. While the impact of age on circulating testosterone levels (total, bioavailable and free) has been strongly documented, the existence of seasonal variations in testosterone levels remains debated.We investigated whether seasonal variations in serum calculated free testosterone (cFT) levels may translate into variations in the prevalence of low testosterone levels. Diagnosis was on the basis of biochemical determinations and was cross-checked with the prevalence of clinical signs and symptoms of 'andropause', as assessed by the Androgen Deficiency in Aging Males (ADAM) questionnaire.The study recruited 5028 men aged 50 years and over from September 2000 to January 2003. Their serum FT levels were assessed and they completed the French ADAM test. Men were considered eugonadal when cFT wasor =70 ng/l. The ADAM test was scored as described originally. The prevalence of 'andropause', diagnosed by the two methods, was compared throughout the year, on a month by month basis.The percentage of subjects with cFT levels below 70 ng/l increased significantly with age (P0.001). Serum cFT levels (mean [SD]) varied significantly with the month of sampling (P0.0001), the highest (88.1 [30.2] ng/l) and lowest (76.9 [28.0] ng/l) mean values occurring in April and in October, respectively. Conversely, the prevalence of testosterone deficiency (cFT70 ng/l) reached a peak in October (45.7%) and a nadir in April (29.7%). Although the prevalence of 'andropause', based on the ADAM questionnaire, increased significantly with age (P0.0001), no influence of the month of the year was noticed.Our results confirm a progressive age-related decline in FT levels. The monthly variations in serum FT values, observed throughout the year, do not show a major seasonal rhythm in elderly community-dwelling males, since the magnitude of the variations (15%) remains marginal. This slight variation may, however, have an impact on the number of elderly men diagnosed with Partial Androgen Deficiency in Aging Males (PADAM).

The aim of the present study was to investigate cognitive effects of a continuous, vertical extremely low frequency (ELF) magnetic field (MF) of 20 and 400 microT 50 Hz in healthy young men during performance on cognitive tests. Thirty-two volunteers (20-30 years old, mean 22.6 +/- 2.2 years) participated in this double blind study. The test protocol consisted of a set of tests: divided attention, flexibility, memory updating, digit span, digit span with articulary suppression, and time perception. The total duration of the exposure was 65 min. Participants were assigned four sessions: three conditions in the helmet (sham exposure, 20 and 400 microT) and one condition out of the helmet (to control the expectancy effect). No effect of MF exposure was observed on performance.

OBJECTIVE: To date, serum free testosterone measurement is considered to be the gold standard for the diagnosis of hypogonadism in elderly males but it is not available to all subjects suspected of a decrease in testicular function. Therefore, we evaluated whether the Androgen Deficiency in Aging Males (ADAM) questionnaire, in its original or in a modified 'quantitative' version (qADAM), could be used as a surrogate to biochemical determinations for the identification of hypogonadism in elderly males. METHODS: 5028 men, aged 50-70 years, spontaneously consulting for the assessment of their gonadal function were studied. ADAM and qADAM, allocating a value of 1 point for any positive answer to each of the 10 questions of the ADAM test, were assessed for their ability to discriminate between males with free testosterone levels below or above 70 ng/l. RESULTS: The sensitivity and specificity of the ADAM score were 81% and 21.6% respectively. The use of ADAM resulted in an appropriate classification of our population in normal or hypogonadal subjects in 44.5% of the cases. The area under the receiver operating characteristics (ROC) curve for the qADAM (0.529) revealed a highly marginal interest of this quantitative approach compared with the original scoring system. CONCLUSIONS: The ADAM test has a high sensitivity to identify aging males with low free testosterone levels. However, due to its lack of specificity, this test cannot be used as a surrogate to serum free testosterone testing for the identification of androgen deficiency in elderly, community-dwelling males.

Chez les hommes âges, il existe une decroissance progressive du taux de testosterone. Apres 50 ans, la chute de ce taux est beaucoup plus marquee et peut entrainer une variete de signes cliniques incluant une deficience sexuelle, une baisse de la force musculaire, une anemie, des symptomes depressifs. Dans plusieurs cas, il reste a demontrer que ces symptomes sont la consequence du deficit androgenique. Sous traitement substitutif, ces symptomes peuvent regresser. Il existe une augmentation progressive de la SHBG (Sex Hormone Binding Globulin) avec l’âge. Le diagnostic de deficit androgenique necessite de prendre en compte la forme bioactive de la testosterone (c’est-a-dire testosterone libre+testosterone liee a l’albumine). De nombreux tests ont ete realises pour detecter la deficience androgenique. La plupart de ces tests ont une bonne sensibilite mais une faible specificite; ceci est du a l’interference de la depression independamment des androgenes et du niveau de qualite de vie.

For more than 30 years, growth hormone (GH) has been observed to be preferentially secreted during deep, slow-wave sleep (SWS). However, the mechanisms that underlie this robust relationship that links anabolic processes in the body with behavioral rest and decreased cerebral metabolism remain to be elucidated. Current evidence indicates that GH secretion during the beginning of sleep appears to be primarily regulated by GH-releasing hormone (GHRH) stimulation occurring during a period of relative somatostatin withdrawal, which also is associated with elevated levels of circulating ghrelin. Apparently, two populations of GHRH neurons need to be simultaneously active to stimulate, in a coordinated fashion, SWS and pituitary GH release. Pharmacological interventions that are capable of increasing the duration and/or the intensity of SWS such as oral administration of gamma-hydroxybutyrate (GHB), also increase the rate of GH release. Because the normal negative feedback exerted by GH on central GHRH is inoperative in patients with GH deficiency, it is possible that the decreased energy levels and fatigue often reported by GH-deficient adults partly reflect an alteration in sleep-wake regulation. Preliminary data from a sleep study of adults with GH deficiency using wrist actigraphy for 6 nights at home and polysomnography in the laboratory indeed show decreased total sleep time and increased sleep fragmentation in GH-deficient patients as compared with normal controls.

Rationale: Flesinoxan is a highly potent and selective 5-HT1A agonist. In a recent study, in normal volunteers, flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Objectives: In order to better define the role of 5-HT receptor subtypes in response to flesinoxan, we assessed the influence of 5-HT1A and 5-HT2 antagonists on hormonal and temperature responses to flesinoxan. Methods: Hormonal and temperature responses were studied in 6 volunteers with or without pretreatment with pindolol (30 mg p.o.), a 5-HT1A antagonist, or ritanserin (10 mg p.o.), a selective 5-HT2 antagonist, using a double-blind crossover design. Results: Pindolol significantly antagonized ACTH, PRL, GH and temperature responses to flesinoxan and ritanserin exhibited similar activity on PRL and ACTH responses. Conclusions: These results show the role of 5-HT1A mechanisms in the PRL, ACTH, GH, and temperature responses to flesinoxan, and the role of 5-HT2 mechanisms in PRL and ACTH responses. Therefore, they confirm the interest of flesinoxan as a 5-HT neuroendocrine probe.

Neurohypophysial oxytocin (OT) and vasopressin (VP) genes are transcribed in thymic epithelium, while immature T lymphocytes express functional neurohypophysial receptors. Neurohypophysial receptors belong to the G protein-linked seven-transmembrane receptor superfamily and are encoded by four distinct genes,OTR,V1R,V2RandV3R. The objective of this study was to identify the nature of neurohypophysial receptor in thymic T cell subsets purified by immunomagnetic selection, as well as in murine thymic lymphoma cell lines RL12-NP and BW5147.OTRis transcribed in all thymic T cell subsets and T cell lines, whileV3Rtranscription is restricted to CD4+CD8+and CD8+thymic cells. NeitherV1RnorV2Rtranscripts are detected in any kind of T cells. The OTR protein was identified by immunocytochemistry on thymocytes freshly isolated from C57BL/6 mice. In murine fetal thymic organ cultures, a specific OTR antagonist does not modify the percentage of T cell subsets, but increases late T cell apoptosis further evidencing the involvement of OT/OTR signaling in the control of T cell proliferation and survival. According to these data,OTRandV3Rare differentially expressed during T cell ontogeny. Moreover, the restriction ofOTRtranscription to T cell lines derived from thymic lymphomas may be important in the context of T cell leukemia pathogenesis and treatment.

In this study, serum melatonin and urinary 6-sulfatoxymelatonin (aMT6s) were measured in 14 major depressive inpatients, compared to 14 matched controls according to age, gender, season and hormonal treatment in women. Moreover, the relationship between serum melatonin and urinary aMT6s levels was analysed in the two groups. Results indicated that the two groups of subjects showed a clear melatonin rhythm without significant difference in the mean level of melatonin or aMT6s, in the area under the curve of melatonin or in the melatonin peak. However, the time of the nocturnal melatonin peak secretion was significantly delayed in depressive subjects as compared to healthy controls. Moreover, the depressed patients showed urinary aMT6s concentrations enhanced in the morning compared to night time levels, while these concentrations were lowered from the night to the morning in the control group. These results suggest that the melatonin production is phase-shifted in major depression.

Les alterations hormonales de l’homme vieillissant representent un sujet d’interet croissant, aux enjeux importants lies au developpement attendu de cette population d’hommes âges de plus de 50 ans. Les preoccupations actuelles concernent essentiellement le declin des androgenes chez l’homme vieillissant (androgen decline in the aging male: «ADAM»), ou deficit partiel en androgenes de l’homme vieillissant (partial androgen deficiency of the aging male: «PADAM»), communement appelee «andropause» en France. Si les connaissances au sujet du deficit androgenique de l’homme âge ont progresse, elles sont encore incompletes, parfois confuses, et certains points concernant le traitement androgenique substitutif restent controverses. C’est pourquoi l’International Society for the Study of the Aging Male (ISSAM) a juge opportun de faire le point sous la forme d’une serie de recommandations pratiques et officielles concernant le diagnostic, le traitement et la surveillance de l’hypogonadisme de survenue tardive chez l’homme. Le but de ce travail est de presenter ces recommandations internationales recentes, sous la forme de leur traduction francaise, et de les commenter.

This study examined the psychological symptomatology of men diagnosed with andropause and the association between calculated free testosterone (T) and depressed mood, anxiety and quality of life. Subjects were 153 men, aged 50-70 years, who participated in a screening of andropause. Total testosterone, FSH, LH and SHBG levels were measured. Depressed mood was assessed with the Carroll Rating Scale, anxiety with the "anxiety-insomnia" dimension of the General Health Questionnaire, and quality of life with the World Health Organisation Quality of Life questionnaire. The results showed that levels of free T decreased with age, whereas FSH and LH increased. Carroll Rating Scale scores were higher among hypogonadal subjects, but the mean score was low and not pathological. A negative correlation was observed between severity of depression as assessed by the Carroll Rating Scale and free T levels. However, subjects with a significant score on this scale did not exhibit different free T levels compared to subjects with a non-significant depressive score. Anxiety and quality of life did not differ between hypogonadal and eugonadal subjects. The present study therefore suggests that andropause is not characterised by specific psychological symptoms, but may be associated with "depressive symptoms" that are not considered as pathological.

Rationale. Flesinoxan is a highly potent and selective 5-HT1A agonist and appears to be a potentially interesting neuroendocrine serotonergic probe. Objectives. We assessed hormonal (ACTH, cortisol, prolactin and growth hormone) and temperature responses to flesinoxan in normal volunteers. Methods. In a double-blind placebo-controlled study, single doses of 0.5 mg and 1 mg were injected over 10 min into 12 healthy male volunteers at 1-week intervals. Temperature and hormonal responses were measured at times –30, 0, 15, 30, 60, 90, and 120 min. Results. Flesinoxan induced a significant and dose-dependent increase in adrenocorticotropic hormone (ACTH), cortisol, prolactin (PRL), growth hormone (GH) and a decrease in body temperature. Tolerance to flesinoxan was excellent. Conclusions. These results showed the role of 5-HT1A mechanisms in the PRL, ACTH, cortisol, GH, and temperature responses to flesinoxan. In the present study, flesinoxan appears a very promising serotonergic neuroendocrine probe.

Out of 29 men asking for a sex-change, 16 reported clinical anamnesis criteria for transsexualism according to the DSM-III–R, a more restrictive diagnosis than the DSM-IV gender dysphoria diagnosis. In addition, all the subjects had taken an MMPI which, of course, did not contribute to the transsexualism diagnosis but which served to describe their personalities. The 16 subjects diagnosed as transsexual and the 13 who did not qualify for this diagnosis were compared on the basis of personality variables measured by the MMPI. Certain differences became evident. The transsexuals systematically complied to cultural stereotypes of femininity without any uneasiness, whereas the nontranssexuals could be subdivided into two groups, those with a vague sense of ill-being linked to a pronounced feminine identity or those with only a slight feminine identity and who showed no particular difficulties.

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile.

Concern about the health effects of extremely low frequency (ELF) magnetic fields (MF) has been raised by epidemiological studies indicating an association between certain cancers and living near power lines or working in high electric field environments. Alterations in pineal function have been proposed as a mechanism through which power-frequency MFs may interact with living organisms. A double blind laboratory study was performed to evaluate daytime exposure effects of 100 microT root mean square (rms) 50 Hz MF. Three head exposure sessions of 30 min each were performed: sham, continuous, and intermittent (15 s on/off cycles) MFs were presented to each subject in early or late afternoon (13:30 or 16:30 hr). Twenty-one healthy male volunteers (20-27 yr old) participated in these 3-weekly experimental conditions. Blood samples were drawn for serum melatonin measurement, hourly at night (from 20:00 to 07:00 hr) under controlled environmental conditions. Urinary excretion of 6-sulfatoxymelatonin (aMT6s), the main melatonin metabolite, was measured for a 17 hr period, by means of urine samples taken at 19:00 hr (14:00-19:00 hr "afternoon period"), 23:00 hr (19:00-23:00 hr "evening period"), and 07:00 hr, day 2 (23:00-07:00 hr day 2 "night-time period"). There were no significant differences in either plasma melatonin or in aMT6s excretion profiles in the three experimental conditions. However, a tendency for a smaller increase of night-time urinary aMT6s after continuous MF exposure was found (P=0.08) particularly in men with the lower excretion rate of aMT6s ("Low Group") (P=0.07). We conclude that this study does not indicate that daytime acute MF exposure influences either melatonin secretion or aMT6s excretion. Inter-individual differences in pineal production of melatonin, however, have to be taken into account in further studies.

The technical possibility of surgical sex change has opened up a debate concerning the legitimacy and utility of carrying out such an intervention at the request of the transsexual. Diagnostic, psychological, medical and ethical arguments have been brought forth, both for and against. Nonetheless, anatomical transformation by surgical means has currently become a practice as the frequency of serious gender identity disorders is constantly progressing. After a brief introduction, the present paper will consider typological, aetiological and epidemiological aspects of transsexualism. Treatment of the sex change applicant is then defined and discussed in terms of psychological, psychiatric, endocrinological and surgical aspects. Finally, the question of post-operation follow-up will be examined.

Oxytocin (OT) and vasopressin (VP) are very similar neurohypophyseal peptides. While VP is known as an ACTH stimulating factor synergistic to CRF since two decades, the inhibiting activity of OT, first demonstrated in the human, is now confirmed in various species including mouse and rat!It is likely that endogenous oxytocinergic system which can be activated by physiological and/or pharmacological manipulation can "buffer" the stress activated vasopressin-ACTH-cortisol action. Since VP and OT share also opposite action on cognitive function, those two "sister" neuropeptides might be considered as "ago-antagonist" or "ying-yang" neurohormones!

The use of CNV in clinical practice requires the choice of a standardised protocol, the constitution of reference normative data and the consideration of intra- and interindividual variability. For this purpose, we recorded CNV in 86 control subjects (44 men and 42 women, 18 to 62 years old (mean age = 34 +/- 13 years) during a reaction time paradigm with a warning signal and a 1-second S1-S2 interval. Moreover, the role of inter-stimulation interval was analysed in a group of 12 subjects through the comparison of recordings made with 1- and 3-second intervals. The CNV amplitude, its morphology and topographic distribution as well as its resolution mode and evolution through the recording were studied. The subjects' performances and their interactions with electroencephalographic data were also included in the analyses. Our results underscore the contribution of age and gender and psychological factors to CNV variability. CNV amplitude (both M1 and M2) increased and changed topographic distribution toward more central sites in older. Men had faster reaction times than women and lower post-S1 P300. Moreover, the life events-related stress and the subject's current anxiety level were accompanied by a decreased CNV amplitude.

Paraneoplastic secretion of the lactation-inducing hormone oxytocin (OT) has been reported in about 30% of cases of small cell carcinoma of the lung (SCCL). In order to investigate the role of OT in the biology of SCCL tumours, a specific enzyme-immunoassay (EIA) for OT, which can be applied to both human plasma and culture medium, has been developed. OT EIA is performed on 96-well microtiter plates coated with a rabbit polyclonal antibody (Ab) anti-OT (04). This antibody does not exhibit any significant cross-reactivity either with vasopressin (VP) or with vasotocin (VT). The immunological reaction involving Ab anti-OT is a competition between the tracer (biotinylated OT) and synthetic OT (standard curve) or OT present in biological samples. In order to limit interference induced by plasma proteins, plasma samples are filtrated by a one-step centrifugation on centricon YM-3 (cut-off 3000 Da). After plasma filtration, 90.7 +/- 5.1 (SD) % (n = 22) immunoreactive (IR) OT is recovered. The sensitivity of OT EIA is 1 pmol/L, while intra- and inter-assay coefficients of variation (CV) are around 3.41% and 2.84%, respectively. In healthy volunteers, plasma IR OT is 7.28 +/- 4.49 (SD) pmol/L (n = 32) with no gender difference. As shown by the data both from plasma of SCCL patients and from supernatants and cell contents of SCCL cell lines, this EIA procedure offers a novel, reproducible, specific and sensitive method for the measurement of IR OT.

Tobacco smoking is considered a major risk factor for the development and progression of periodontal diseases (Haber, J. and Wattles, J. (1994). J. Periodontol., 64, 16-23). The purpose of this study was to determine the effects of nicotine on rat gingival fibroblasts (RGF) cultured in vitro. After ether anesthesia, rat gingival tissues were obtained from the attached gingiva of a Wistar rat. Small fragments of gingiva were maintained in culture in Petri dishes. Fibroblasts developing from these explants were collected to obtain monolayer cultures. After the fourth passage (T4), cells were supplemented with nicotine at various concentrations. Control and treated cells were examined under phase contrast or transmission electron microscopy. They were compared as regards their DNA content, mitochondrial activity, collagen and protein synthesis, and cell death by apoptosis or necrosis. Nicotine from 0.05 microM to 1 mM did not affect the DNA content or protein and collagen synthesis. At concentrations between 3 and 5 mM, growth was significantly diminished and the survival rate reduced. Ultrastructural analysis revealed dilated mitochondria and vacuolization in treated cells, suggestive of necrosis, but increased apoptosis was also revealed by cytometry. On the basis of this in vitro study, it appears that tobacco, through its component nicotine, may directly affect various functions of RGF.

Two double-blind studies were performed to examine magnetic field (MF) exposure effects and to determine the impact of temporal variation (continuous vs. intermittent exposure) of 100 mu T(rms) 50 Hz MF diurnal exposure on psychological and psychophysiological parameters in healthy humans. Three cephalic exposure sessions of 30-min, i.e., sham, continuous, and intermittent (15 s ON/OFF cycles) MF conditions, were involved. Each subject participated in all sessions, which were spaced at 1-wk intervals. In each session, mood ratings and performance measures were obtained before, during, or after exposure and several electrophysiological data (event-related brain potentials [ERP]) were recorded after each exposure session. These criteria were chosen to evaluate sensory functions as well as automatic and voluntary attentional processes. In experiment 1, 21 healthy male volunteers (20 to 27 years of age) were studied. Ten subjects were exposed at 13:30 h, and 11 subjects were exposed at 16:30 h. Statistically significant changes in the amplitude of ERP were observed after MF exposure in the dichotic listening task, indexing selective attention processes. Eighteen of the 21 original male volunteers took part in experiment 2, undertaken to better understand the results related to information processing involved in selective attention and control for ultradian rhythmicity. Exposure time for all the subjects was at 13:30 h. The analysis of the data again revealed significant amplitude changes of the ERP recorded in the dichotic listening task. Moreover, they demonstrated ERP latency and reaction time slowing in the oddball paradigm, a visual discrimination task after real MF exposure. These results also indicate that a low level 50 Hz MF may have a slight influence on event-related potentials and reaction time under specific circumstances of sustained attention.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610-amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations ( D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population. Hum Mutat 13:54-60, 1999. (C) 1999 Wiley-Liss, Inc.

The expression of members of the IGF system in a mesothelioma from a patient suffering from hypoglycemia, in term placenta and HT29 colon adenocarcinoma cells were compared. Very high levels of IGF-II mRNA and protein were detected in the mesothelioma. Moreover, half of the IGF-II protein took the high-molecular-weight form. We also analyzed the parental imprinting status and the promoter usage of the IGF-II gene. Our results showed loss of imprinting (LOI) in the mesothelioma while the imprinting was maintained in HT29 cells, expressing moderate levels of the transcript. Promoter P4 was active in the three tissues we analyzed, whereas IGF-II mRNA transcription from promoter P3 was only detected in the mesothelioma and the placenta, expressing comparably high levels of the transcript. IGF-II gene structure was identical in the analyzed tissues and cells. The type-I receptor mRNA expression was very low in the tumor. IGFBP-2, -4 and -5 mRNAs were detected in the mesothelioma, while IGFBP-2, -3 and -5 transcripts were detected in the placenta. IGFBP-1 and -6 transcripts were not detected.

(2005). Investigation, treatment and monitoring of late-onset hypogonadism in males. The Aging Male: Vol. 8, No. 2, pp. 56-58.

ObjectivesWe previously reported that adult patients with GH deficiency (GHD) due to a confirmed or likely pituitary defect, compared with healthy controls individually matched for age, gender, and BMI, have more slow-wave sleep (SWS) and higher delta activity (a marker of SWS intensity). Here, we examined the impact of recombinant human GH (rhGH) therapy, compared with placebo, on objective sleep quality in a subset of patients from the same cohort.DesignSingle-blind, randomized, crossover design study.MethodsFourteen patients with untreated GHD of confirmed or likely pituitary origin, aged 22–74 years, participated in the study. Patients with associated hormonal deficiencies were on appropriate replacement therapy. Polygraphic sleep recordings, with bedtimes individually tailored to habitual sleep times, were performed after 4 months on rhGH or placebo.ResultsValid data were obtained in 13 patients. At the end of the rhGH treatment period, patients had a shorter sleep period time than at the end of the placebo period (479±11 vs 431±19 min respectively;P=0.005), primarily due to an earlier wake-up time, and a decrease in the intensity of SWS (delta activity) (559±125 vs 794±219 μV2respectively;P=0.048).ConclusionsFour months of rhGH replacement therapy partly reversed sleep disturbances previously observed in untreated patients. The decrease in delta activity associated with rhGH treatment adds further evidence to the hypothesis that the excess of high-intensity SWS observed in untreated pituitary GHD patients is likely to result from overactivity of the hypothalamic GHRH system due to the lack of negative feedback inhibition by GH.

We investigated the effects of oral testosterone undecanoate (TU) on bone mineral density (BMD), lean body mass (LBM) and body fat mass (BFM) in aging men with symptomatic testosterone deficiency (TD).Three hundred twenty-two men ≥50 years with TD symptoms and calculated free testosterone0.26 nmol/L participated in a multicenter, double-blind, placebo-controlled trial. Patients were randomized to placebo, oral TU 80 mg/d, oral TU 160 mg/d, or oral TU 240 mg/d, administered as divided doses with normal meals. BMD of the hip and lumbar spine were evaluated by dual energy X-ray absorptiometry (DEXA), and body composition (LBM and BFM) by whole body DEXA.Oral TU significantly increased BMD at Month 12 at the lumbar spine (240 mg/d), total hip (240 mg/d), and trochanter and intertrochanter (160 and 240 mg/d) compared with placebo. Oral TU significantly increased LBM at Months 6 and 12 for all oral TU groups compared with placebo. BFM significantly decreased at Month 6 (all oral TU groups) and Month 12 (160 mg/d) compared with placebo. The effects on BMD and body composition showed a clear dose response.Treatment with oral TU led to improvement in BMD, LBM and BFM in aging men with symptomatic TD.

Among other confounding factors, the influence of the intake of estrogen-containing oral contraceptives on the dexamethasone suppression test (DST) results has never been specifically studied. Therefore, we performed 1 mg DST's in 14 healthy women taking oral contraceptives and 14 age-matched women taking no oral contraceptives. Mean 0800h basal total cortisol was significantly higher among the women taking contraceptives than in the control group, whereas mean free cortisol did not significantly differ. At 1600h following DST, no significant difference existed between the two groups. Two subjects taking contraceptives and one control subject were considered DST nonsuppressors. These results confirm the powerful influence of oral contraceptives on basal total cortisol levels but suggest a lack of significant influence on DST results.

The dual physiological role of the thymus in T cell positive and negative selection appears prominent in the establishment of appropriate host immune defenses. However, the cellular and molecular mechanisms underlying those thymic functions begin only to be understood. On the basis of our previous investigations about the thymic expression of different neuroendocrine-related signals, we have advanced a model which transposes at the peptide level the intervention of this primary lymphoid organ in both T cell positive and negative selective processes. There is now ample evidence that the thymic subcapsular and medullary epithelium is the site for synthesis of neurohypophysial (NHP)-related peptides (reviewed in Geenen et al., 1992a). We have also demonstrated that the epithelial component of thymic "nurse" cells (TNC) synthesizes NHP-related peptides and expresses a neuroendocrine-like phenotype (Geenen et al., 1988a). This observation was a remarkable example of the intimate neuroendocrine-immune interactions that take place during T cell ontogeny. Further immunocytochemical analyses have confirmed that one dominant NHP-related epitope belongs to the oxytocin (OT) lineage of the NHP peptide superfamily (Robert et al., 1991, 1992). The intrathymic coexpression of this OT-like epitope with a neurophysin protein domain is a strong argument for a local synthetic process similar to the hypothalamo-NHP one. However, the absence of ir-OT in secretory granules of thymic epithelial cells (TEC), as well as of NHP-related peptides in the supernatant of TEC cultures questioned the application to the thymus of the classical neurosecretory model established for hypothalamic magnocellular neurons (Scharrer & Scharrer, 1944).(ABSTRACT TRUNCATED AT 250 WORDS)

Low energy and fatigue are frequent complaints in subjects with GH deficiency (GHD). Because interrelations between sleep and GH regulation are well documented, these complaints could partly reflect alterations of sleep quality.The objective of the study was to determine objective and subjective sleep quality and daytime sleepiness in adult GHD patients.Thirty patients, aged 19-74 yr, with untreated GHD (primary pituitary defects confirmed or likely in 26 patients, hypothalamic origin in four patients), and 30 healthy controls individually matched for gender, age, and body mass index participated in the study. Patients with associated pituitary deficiencies (n = 28) were on hormonal replacement therapy.Polygraphic sleep recordings, assessment of Pittsburgh Sleep Quality Index, and Quality of Life Assessment for GHD in Adults were measured.Irrespective of etiology, GHD patients had a Pittsburgh Sleep Quality Index score above the clinical cutoff for poor sleep and lower Quality of Life Assessment for GHD in Adults scores than controls, with tiredness being the most affected domain. Patients with pituitary GHD spent more time in slow-wave sleep (SWS) and had a higher intensity of SWS than their controls. Among these patients, older individuals obtained less total sleep than controls, and their late sleep was more fragmented. Contrasting with pituitary GHD, the four patients with hypothalamic GHD had lower intensity of SWS than their controls.GHD is associated with sleep disorders that may be caused by specific hormonal alterations as well as with poor subjective sleep quality and daytime sleepiness. Disturbed sleep is likely to be partly responsible for increased tiredness, a major component of quality of life in GHD.

Apomorphine challenge tests (0.5 mg SC) were performed in 14 normal male volunteers and in 9 male schizophrenic inpatients, drug-free for at least 2 wk. In the normal volunteers, apomorphine induced an increase of serum growth hormone (GH) (maximum at 40 min), of vasopressin-neurophysin (hNpI) (maximum at 20 min), and oxytocin-neurophysin (hNpII) (maximum at 20 min). The release of neurophysins was independent of digestive side effects. In the schizophrenics, the GH level and release pattern were similar to those in the controls. The basal level of hNpI was reduced (t0: 0.42 +/- 0.1 ng/ml in the schizophrenics and 0.66 +/- 0.05 ng/ml in the controls, p < 0.02). In contrast, the basal level of hNpII was increased (3.34 +/- 0.04 ng/ml in the schizophrenics to 0.92 +/- 0.21 ng/ml in the controls, p = 0.001). The response to apomorphine was blunted, with no significant release of hNpI or of hNpII. Although the hNpII data are consistent with an increased dopaminergic tone, the psychopathological meaning of the increased basal oxytocinergic and decreased vasopressinergic functions remains to be defined.

SummaryThe usefulness of the dexamethasone suppression test (DST) in the prediction of treatment response to selective antidepressants was tested in 56 major depressive inpatients. Following DST, patients were randomly assigned to treatment by either nomifensine, a catecholaminergic antidepressant, or zimeldine, a serotonergic antidepressant during a 3-week period and assessed by means of the second part of the Clinical Global Impressions (CGI-2). No significant difference was present between the 27 DST suppressor and the 29 DST non-suppressor patients in their overall clinical outcome. Moreover, no preferential response to nomifensine or zimeldine was noted in any of the two groups defined according to DST status. Therefore, these results do not support the usefulness of the DST in the prediction of the treatment response to antidepressants in general and to selective antidepressants in particular.

Oxytocin (OT) is implicated in stress reduction as well as in social behavior. It inhibits the stress-induced activity of the hypothalamic-pituitary adrenal axis responsiveness. OT is involved in social affiliation, sexual and maternal-infant binding, anxiety, mood, feeding control and memory. Several lines of evidence suggest a role of OT in psychiatric disorders. Various psychiatric disorders are strongly influenced by social variables, such as panic attacks, depression and early childhood autism, and seem to exhibit a particularly close connection with the brain dynamics that underlie social emotions. This paper proposes an overview of OT in psychiatric disorders through the links with the stress response and prosocial behavior.

ObjectiveTo investigate the effects of oral testosterone undecanoate (TU) on symptoms associated with late-onset hypogonadism (LOH).DesignMulticenter, randomized, double-blind, placebo-controlled.MethodsThe study was performed in 14 study centers in seven European countries. Men ≥50 years (n=322) with symptoms of hypogonadism and testosterone deficiency (calculated free testosterone ResultsTreatment of mild-to-moderate LOH symptoms in subjects with borderline hypogonadism with oral TU resulted in an improved total AMS score at month 6, but differences between groups were not statistically significant. There was greater improvement in subjects P=0.001), but baseline testosterone level had no influence on treatment response. The AMS sexual symptoms domain improved with oral TU 160 mg/day at months 6 (P=0.008) and 12 (P=0.012) compared with placebo, but not with 80 and 240 mg/day. Treatment was well-tolerated and there were no between-group differences in adverse events or drop-out rates.ConclusionsIn one of the largest placebo-controlled studies of testosterone therapy in LOH, oral TU did not improve total AMS score in subjects with mild-to-moderate symptoms compared with placebo, except the sexual symptom sub-domain where a modest improvement was reported with oral TU 160 mg/day.

Demographic data clearly demonstrate that the percentage of the population in the older age group is increasing. Androgen deficiency in the aging male has become a topic of increasing interest and debate throughout the world. Cross-sectional and longitudinal data indicate that the testosterone falls progressively with age and that a significant percentage of men over the age of 60 years have serum testosterone levels that are below the lower limits of young adult (age 20–30 years) men (1–4). The principal questions raised by these observations are whether older hypogonadal men will benefit from testosterone treatment and what will be the risks associated with such intervention. The past decade has brought evidence of benefit of androgen treatment of hypogonadal men on multiple target organs and the recent studies show short-term beneficial effects of testosterone in older men that are similar to those in younger men. This has been comprehensively reviewed and summarized by the Institute of Medicine in ‘Testosterone and Aging: Clinical Research Directions’ (5). Long-term data on the effects of testosterone treatment in the older population are limited mainly to effects on body composition and bone mass (6–11). Key questions of the effects of testosterone on patient reported outcomes and functional benefits that may retard physical or mental frailty of the elderly or improve the quality of life are not yet available. Specific risk data on the prostate and cardiovascular systems are needed.

Inhibition of ethanol tolerance by oxytocin has been demonstrated previously using the hypothermic effect only. The purpose of the present experiment was to investigate the effect of oxytocin on the development of tolerance to ethanol-induced hypothermia, myorelaxation and akinesia in mice. Four groups of mice received daily intraperitoneal injections of saline or oxytocin (0.005 mg) plus saline or ethanol (2 g/kg). The peptide was administered 2 hours before ethanol. For five consecutive days, temperature measurements were performed 20 minutes before and after ethanol injection. Myorelaxation and akinesia were evaluated following the second temperature measure. Oxytocin pretreatment, which had no intrinsic effects, resulted in a robust selective attenuation of tolerance to ethanol-induced hypothermia, myorelaxation and akinesia. These results suggest that the mechanisms for peptide modulation are common to these three typical effects of ethanol.