The neuroendocrine thymus: coexistence of oxytocin and neurophysin in the human thymus.

Immunoreactive oxytocin and neurophysin were identified and measured by radioimmunoassay in human thymus extracts. Serial dilutions of extracts paralleled the appropriate standard curves. Thymus-extracted oxytocin and neurophysin eluted in the same positions as reference preparations on Sephadex G-75. Authenticity of oxytocin was confirmed by biological assay and high-performance liquid chromatography analysis. In most instances, thymus contents of oxytocin and neurophysin were far greater than those expected from known circulating concentrations and declined with increasing age. The molar ratio of oxytocin to neurophysin in thymus was similar to that found in the hypothalamo-neurohypophyseal system, which strongly suggested with the other data a local synthesis of oxytocin. These findings indicate the presence of neurohypophyseal peptides in the human thymus and further support the concept of a neuroendocrine function integrated in an immune structure.

[Severe hyponatremia revealing Sheehan's syndrome]. / Une hyponatrémie sévère révélatrice d'un syndrome de Sheehan.

We describe the case of a young woman admitted for severe hyponatremia due to hypopituitarism caused by a Sheehan's syndrome. Sheehan's syndrome is a rare disorder. It develops after obstetrical hemorrhage that causes ischemic necrosis of the pituitary gland. In most cases, illness appears progressively and diagnosis is made after variable delay. Acute syndrome may develop immediately after delivery in some rare cases. Hyponatremia is a frequent manifestation and may be severe. It is principally caused by secondary adrenal failure.

[Neurohypophyseal neuropeptides and unipolar depression: which future?]. / Peptides neurohypophysaires et dépression unipolaire: quel avenir?

Vasopressin (AVP) and oxytocin (OT) are two chemically similar neurohypophyseal neuropeptides which could be involved in mood disorders. Those two sister neuropeptides might be considered as ago-antagonist hormones. They act as neuromodulators of the stress response. AVP is known as an ACTH stimulating factor synergistic to CRH while OT could act as an antagonist of AVP on ACTH secretion. AVP seems to play an important role in the pathophysiology of major depression. Evidence suggests a role for OT as an endogenous antidepressant/anxiolytic hormone. OT release is also an important aspect of the pharmacological action of SSRIs. In addition, their receptors are of growing interest for psychiatric research. A selective AVP V1b receptor, SSR1419415, has been characterized and is endowed with anxiolytic- an and antidepressant-like properties. This paper proposes an overview of neurohypophyseal hormones in major depression.

[Secondary amenorrhea and cerebral ventriculomegaly]. / Aménorrhée secondaire et ventriculomégalie cérébrale.

Cerebral ventriculomegaly and hydrocephalus are not frequently associated with endocrine disorders of the gonadotropic axis. The mechanism of this association is not clarified. The most probable cause is however a partial hypothalamic dysfunction. The examination of the few reported cases is in favour of this explanation. We present the case of a young woman with a cerebral ventriculomegaly and suffering from secondary amenorrhea. Shunt was not necessary from the neurological point of view, the problem of secondary amenorrhea and anovulatory infertility was solved by clomiphen citrate therapy.

Plasma oxytocin levels and anxiety in patients with major depression.

Cerebrospinal fluid and plasmatic levels of oxytocin (OT) have been found to change in mood disorders. In post-mortem studies, the numbers of OT-expressing neurons in the paraventricular nucleus have been reported to be increased. Moreover, OT is considered as an endogenous antistress hormone. It has also revealed antidepressive effects. OT may contribute to the dysregulation of the HPA system in major depression. The aim of the study was to assess a possible relationship between anxiety and plasma oxytocin (OT) levels in depressive patients. Severity of depression was estimated with the Hamilton Depression Rating Scale and anxiety by using the Spielberger State-Anxiety Inventory. Results showed a significant negative correlation between oxytocin and the scored symptoms depression (r=-0.58, p=0.003) and anxiety (r=-0.61, p=0.005).

[Hormonal treatment in transsexual patients. Metabolic consequences]. / Le traitement hormonal des patients transsexuels et ses conséquences métaboliques.

Transsexualism is a sexual identity disorder distinguished by the extreme conviction of belonging to the opposite sex with a total disharmony in the original sex. Diagnosis is established when patients respond to three criteria (DSM-IV): 1) Desire to live and to be accepted as members of opposite sex; 2) Presence of sexual identity disorder for minimal two years; 3) Lack of mental disease or chromosomal anomalies. When diagnosis is confirmed, hormonal treatment can be started and so, improve the secondary sexual characters of selected sex. For patients F-M, treatment is composed of testosterone, most commonly esters of testosterone. For patients M-F, treatment consists of estrogens. These estrogens are frequently associated to an anti-androgen (cyproterone acetate) in the pre-reassignment phase. Avoiding the hepatic way, transdermal form is recommended. Hormonal treatments are not devoid of secondary effects: the most frequent one is venous thromboembolism. Considering contraindications and potential complications, each patient must be selected carefully. The endocrinological follow-up is essential and necessary.

[Rhabdomyolysis and hypothyroidism]. / Le cas clinique du mois. Rhabdomyolyse et hypothyroïdie.

We describe the case of a 29 year old patient who presented severe myalgias and asthenia for 3 months. First biological assessment revealed muscular lysis and raised transaminases. The following complementary screening showed major hypothyroidism with the presence of anti-microsomes antibodies, a carpian canal syndrome and a left ventricular systolic dysfunction. A diagnosis of hypothyroidic rhabdomyolysis consecutive to a Hashimoto disease was then mash. Patient was treated by hormonal thyroid substitution with a progressive improvement of muscular symptoms to complete recovery, and a concomitant normalization of cardiac and thyroid functions.

[Oxytocin and maternal stress during the post-partum period]. / Ocytocine et stress de la mère au cours de la lactation en post-partum. L'ocytocine est-elle impliquée dans la confiance en soi de la mère allaitante? Revue de la littérature.

Oxytocin is required for lactation by promoting milk expulsion. Oxytocin has also been reported to exert a positive role in social attachment. The postpartum period has been shown to be crucial for maternal behavior initiation, and required self-trust reinforcement. However, this period is also remarkable for the high risk exposure of either psychic or physical stress. A negative impact on young mother is suspected, both in the short, medium or long term, which can even be deleterious for child-mother relationships. During lactation in female rats and sheep, oxytocin production has been proved to decrease stress-induced hormonal changes and later consequences. In human beings, only the first hour after breast-feeding seems to protect against physical or psychic stress. Oxytocin improves the stress-induced response by reducing the ACTH and cortisol secretion thus representing a potential therapeutic pathway in post-partum pathologies such as depression. Thus, this review of recent literature about oxytocin and stress during post-partum period, leads to the assumption that oxytocin, at the moment of installation of breastfeeding, acts not only on the physiological condition, but also on the psychic condition of the mother.

Hemodynamic changes induced by laparoscopy and their endocrine correlates: effects of clonidine.

OBJECTIVES: We investigated endocrine correlates of the hemodynamic changes induced by carbon dioxide pneumoperitoneum (PNO). We then studied whether clonidine might modulate the hemodynamic changes induced by PNO by reducing release of catecholamines and vasopressin. BACKGROUND: Both mechanical and neurohumoral factors contribute to the hemodynamic changes induced by carbon dioxide PNO. Several mediators have been proposed, but no study has correlated hemodynamic changes with changes in levels of these potential mediators. METHODS: We conducted two studies, each including 20 healthy patients scheduled for elective laparoscopic cholecystectomy. In the first study serial measurements of hemodynamics (thermodilution technique) were done during laparoscopy and after exsufflation. Plasma concentrations of cortisol, catecholamines, vasopressin, renin, endothelin and prostaglandins were measured at the same time points. In the second study patients were randomly allocated to receive 8 microg/kg clonidine infused over 1 h or placebo before PNO. Hemodynamics and plasma levels of cortisol, catecholamines and vasopressin were measured during PNO and after exsufflation. RESULTS: Peritoneal insufflation resulted in a significant reduction of cardiac output (18+/-4%) and increases in mean arterial pressure (39+/-8%) and systemic (70+/-12%) and pulmonary (98+/-18%) vascular resistances. Laparoscopy resulted in progressive and significant increases in plasma concentrations of cortisol, epinephrine, norepinephrine and renin. Vasopressin plasma concentrations markedly increased immediately after the beginning of PNO (before PNO 6+/-4 pg/ml; during PNO 129+/-42 pg/ml; p < 0.05). The profile of vasopressin release paralleled the time course of changes in systemic vascular resistance. Prostaglandins and endothelin did not change significantly. Clonidine significantly reduced mean arterial pressure, heart rate and the increase in systemic vascular resistance. Clonidine also significantly reduced catecholamine concentrations but did not alter vasopressin and cortisol plasma concentrations. CONCLUSIONS: Vasopressin and catecholamines probably mediate the increase in systemic vascular resistance observed during PNO. Clonidine before PNO reduces catecholamine release and attenuates hemodynamic changes during laparoscopy.

Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network.

Ontogenesis of oxytocin (OT) and vasopressin (VP) gene expression and function were investigated in murine thymus. OT and VP transcripts were detected in the thymus on embryonic days 13 and 15, respectively. Corresponding messenger RNAs were evidenced in thymic epithelial cells by in situ hybridization with a neurophysin probe. From all OT and VP receptors, only OTR was expressed by all T-cell subsets, while V1bR was found in double positive and single positive CD8 cells. In fetal thymic organ cultures, OTR antagonist d[D-Tyr(Et)2, Thr4]OVT increased early apoptosis of CD8 cells, while V1bR antagonist (Sanofi SSR149415) inhibited T-cell differentiation, and favored CD8 T-cell commitment.

AVP- and OT-neurophysins response to apomorphine and clonidine in major depression.

A number of studies have reported abnormalities of neurohypophyseal secretions in major depressive disorder. The purpose of the present study was to test the influence of apomorphine and clonidine injections on plasma vasopressin (AVP)-neurophysins and oxytocin(OT)-neurophysins levels, as direct index of posterior pituitary activation in major depression. Apomorphine and clonidine tests were carried out in 25 medication-free depressive patients and 25 age and gender-matched healthy controls. Blood for neurophysins analysis was drawn by venipuncture at t0, t + 20, t + 40, t + 60 and t + 120. Baseline AVP-neurophysins concentrations were significantly lower in depressives (0.12 +/- 0.14 ng/ml) than in healthy subjects (0.24 +/- 2.15 ng/ml) (p < 0.04). The response to apomorphine test revealed a significant reduced response at 20 (p = 0.01), 40 (p = 0.007) and 60 (p = 0.02) and 120 (p = 0.02)min. Following clonidine test, post hoc tests also revealed a significant decrease at 0 (p = 0.04), 20 (p = 0.01), 40 (p = 0.007) and 60 (p = 0.02) and 120 (p = 0.006)min. Concerning OT-neurophysins, no significant differences were found between depressed and controls in response to clonidine or apomorphine injections. Following clonidine and apomorphine, major depressives exhibited a significantly lower peak GH response than controls. The study supports partially the hypothesis of a reduced vasopressinergic activity in depression. Moreover, we did not find any influence of acute apomorphine or clonidine injections on vasopressin-neurophysin or oxytocin-neurophysin in depressive patients.

Expression of preprotachykinin-A and neuropeptide-Y messenger RNA in the thymus.

The preprotachykinin-A gene, the common gene of mRNAs encoding both substance-P (SP) and neurokinin-A (NKA), was shown to be expressed in Sprague-Dawley rat thymus by detection of specific mRNA in gel-blot analyses. In situ hybridization revealed dispersed PPT-A-labeled cells in sections from rat thymus, with a concentration of grains over a subpopulation of cells in the thymic medulla. Also, neuropeptide-Y mRNA-expressing cells were found in the rat thymus, primarily in the thymic medulla. Rat thymic extracts contained SP-like immunoreactivity (SP-LI), and the major part of the immunoreactivity coeluted with authentic SP and SP sulfoxide standards. SP-LI was also detected in human thymus, which contained between 0.09-0.88 ng SP-LI/g wet wt. Evidence for translation of preprotachykinin-A mRNA in the rat thymus was obtained from the demonstration of NKA-LI in thymic cells with an epithelial-like cell morphology. Combined with previous observations on the immunoregulatory roles of tachykinin peptides and the existence of specific receptors on immunocompetent cells, the demonstration of intrathymic synthesis of NKA suggests a role for NKA-LI peptides in T-cell differentiation in the thymus.

[Diabetes insipidus in a patient with small-cell lung cancer: a paradox?]. / Diabète insipide dans le cadre d'un carcinome pulmonaire à petites cellules: un paradoxe?

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.

Additional intranasal oxytocin to escitalopram improves depressive symptoms in resistant depression: an open trial.

The aim of this open trial was to assess the antidepressant/anxiolytic effects of oxytocin used as an adjunct to antidepressant in treatment-resistant depression. Fourteen patients, who have not responded to 40mg of escitalopram, received intranasal synthetic oxytocin during 4 weeks, in association with antidepressant. This is the first open trial study suggesting OT in association with escitalopram significantly reduced scores on Hamilton Depression Rating Scale.

Oxytocin- and vasopressin-induced growth of human small-cell lung cancer is mediated by the mitogen-activated protein kinase pathway.

Malignant growth of small-cell lung carcinoma is promoted by various neuroendocrine autocrine/paracrine loops. Therefore, to interfere with this mitogenic process, it is crucial to elucidate the mechanisms involved. It is known that the oxytocin (OT) and vasopressin (VP) genes, normally transcriptionally restricted in their expression, are activated in small-cell lung cancer (SCLC), concomitantly with expression of their receptors (OTR, V1aR, V1bR/V3R and V2R). The aim of the present study was to characterize, in concentrations close to physiological and pharmacological conditions, intracellular signalling events triggered by OT and VP binding to their specific receptors in SCLC cells and to identify factors mediating OT- and VP-induced mitogenic effects on SCLC. Known agonists for OTR ([Thr4,Gly7]OT) and V1aR (F180), in addition to OT and VP, were able to elicit increases in cytosolic Ca2+ levels and this effect could be blocked using an OTR antagonist (OVTA) or a V1aR antagonist (SR49059) respectively. There was no activation of the cAMP pathway detected after VP, dDAVP (a V2R agonist), or OT treatment. Stimulation of SCLC cells with OT and VP led to an increase of extracellular signal-regulated kinase (ERK) 1/2 phosphorylation, maximal at 5 min, and the subsequent phosphorylation of its downstream target p90 ribosomal S6 kinase (p90RSK). Pre-incubation with OVTA and SR49059, and with inhibitors of phospholipase C (PLC), protein kinase C (PKC), mitogen-activated protein kinase/ERK kinase (MEK) 1/2 and a Ca2+ chelator significantly reduced OT- and VP-induced ERK1/2 phosphorylations. OVTA, SR49059 as well as MEK1/2 and PKC inhibitors also downregulated OT- and VP-induced p90RSK phosphorylation. In [3H]thymidine-uptake experiments, we subsequently observed that PLC, Ca2+, PKC and ERK1/2 are absolutely required for the OT- and VP-stimulated SCLC cellular growth process. In conclusion, the results presented here indicate that OT- and VP-induced mitogenic effects on SCLC are respectively mediated by OTR and V1aR signalling and that this mitogenic signalling passes through the phosphorylation of ERK1/2 and p90RSK in a PLC-, Ca2+-, PKC- and MEK1/2-dependent pathway.

Serum neurophysins during passive assumption of the erect posture in men and during pregnancy: effect of syncope.

A slight but reproducible increase in serum total immunoreactive neurophysin levels (IRN) occurred 30 minutes following passive assumption of the erect posture (tilt test) in 12 men (17%, 2 P is less than .02) and in 6 pregnant women (20%, 2P=NS) who showed normal cardiovascular adaptation during the test and did not suffer syncope. The increase was much more marked in 4 men in whom there was a fall in blood pressure and syncope in assuming the upright posture. An increase of twice the basal level was also found in a pregnant women who experienced syncope, although she was maintained horizontal. Our results show that it is important to ensure the absence of these intercurrent phenomena in the correct interpretation of dynamic clinical tests of neurohypophysial function.

Serum Neurophysins in familial central diabetes insipidus.

Antibovine neurophysin antibodies (anti-bNpI and/or anti-bNpII) are present in certain patients with familial central diabetes insipidus; these are exogenous origin, as they are not present in patients who have not received treatment with crude posterior pituitary extracts over the years preceding the analysis. Immunoreactive neurophysins were detectable in the blood of five patients with familial central diabetes insipidus, and in two of them, the levels increased after a short period of water restriction. There is marked polymorphism of these neurophysins from one serum to another: neurophysin I was consistently absent, while neurophysin II, accessory neurophysins, and other immunoreactive substances not present in normal sera were sometimes present in variable amounts. Immunoreactive AVP was undetectable in the urine of all patients, while immunoreactive OT was found in three of them; the latter substance could, however, be arginine vasotocin. Data are presented suggesting that the association between the biosynthesis of neurophysin I and AVP on the one hand, and neurophysin II and OT on the other hand is maintained in patients with isolated AVP deficiency on the basis of a congenital defect.

Inhibitory influence of exogenous oxytocin on adrenocorticotropin secretion in normal human subjects.

Oxytocin has been suggested to have behavioral effects opposite to those of vasopressin, and exogenous vasopressin is known to induce ACTH release in man. Thus, we tested the influence of exogenous oxytocin on blood levels of ACTH and cortisol during insulin-induced hypoglycemia and after vasopressin injection. Our results demonstrate an inhibitory effect of exogenous oxytocin on ACTH release and support the hypothesis of a reciprocal, balanced modulation of behavioral and neuroendocrine function by the two closely related neurohormones, vasopressin and oxytocin.

Variations of neurohypophysial function in normally cycling women.

Using a neurophysin radioimmunoassay, we have studied basal neurohypophysial function in seven normal women. An increase in neurophysin blood levels has been demonstrated during the ovulatory and/or luteal phase as compared to the follicular phase; these variations are related to the changes in the circulating levels of 17beta-estradiol. The data provide additional evidence for a relationship between estrogens and neurohyprophysial function, as previously shown following exogenous administration of estriol and ethinyl estradiol in man.