Dihydrotestosterone and Leptin Regulate Gonadotropin-Releasing Hormone (GnRH) Expression and Secretion in Human GnRH-Secreting Neuroblasts

IntroductionThe reversal of hypogonadotropic hypogonadism (HH), occurring after discontinuation of testosterone therapy in adolescents with delayed puberty and in a small percentage of adults with congenital HH, suggests a role for androgens in favoring a spontaneous recovery of reproductive function.AimWe investigated the effect of androgens and leptin on gonadotropin-releasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts (FNC-B4).MethodsQuantitative real-time polymerase chain reaction RT-PCR for mRNA expression and radioimmunoassay for GnRH secretion were used. Immunohistochemical studies assessed GnRH protein expression. FNC-B4 migration was analyzed with multiwell Boyden chamber technique.Main Outcome MeasuresEffects of the non-aromatizable androgen dihydrotestosterone (DHT) and leptin in FNC-B4 were tested after 24 and 48 hours.ResultsExposure to increasing concentrations of DHT after 24 hours significantly stimulated GnRH mRNA in FNC-B4. This effect was still present after prolonged exposure (48 hours). Similarly, treatment with leptin significantly induced GnRH mRNA after 24 hours, but not at 48 hours. Interestingly, mRNA for leptin receptors (LEPR) was significantly reduced after 48 hours of leptin, while, at this time point, it was stimulated by DHT. Coincubation for 48 hours with leptin and DHT maintained the stimulatory effect on both GnRH and LEPR mRNA, suggesting that DHT could stabilize the leptin effect by preventing downregulation of LEPR. Similar results were obtained for GnRH protein expression analysis. Moreover, both DHT and leptin increased GnRH release into the culture medium. We also found that DHT or leptin treatment significantly increased FNC-B4 basal migration. As we previously found that GnRH stimulates FNC-B4 migration, we hypothesized that this effect could be mediated by DHT- and leptin-induced GnRH release. Accordingly, the GnRH antagonist cetrorelix inhibited DHT- and leptin-induced migration.ConclusionOur results suggest that androgens (adequate hormonal status) could have a positive effect on GnRH neuronal activity by synergizing with leptin (adequate energy status) in the regulatory mechanisms required for reproductive and sexual fitness. Morelli A, Fibbi B, Marini M, Silvestrini E, De Vita G, Chavalmane AK, Vignozzi L, Filippi S, Forti G, Vannelli GB, and Maggi M. Dihydrotestosterone and leptin regulate gonadotropin-releasing hormone (GnRH) expression and secretion in human GnRH-secreting neuroblasts. J Sex Med 2009;6:397–407.     

ORIGINAL RESEARCH–EPIDEMIOLOGY: Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction

IntroductionSexual dysfunctions are often present in subjects with mood disturbances; however. antidepressants can induce per se sexual dysfunctions.AimTo explore the relationship between the use of selective serotonin reuptake inhibitors (SSRIs), non-SSRIs antidepressants and benzodiazepines (BDZ), hormonal parameters, and reported sexual dysfunction (as assessed by the Structured Interview on Erectile Dysfunction [SIEDY]) in male subjects with comparable psychopathological symptoms (as assessed by the Middlesex Hospital Questionnaire [MHQ] a self-reported test for the screening of mental disorders in a non-psychiatric setting).MethodsA consecutive series of 2,040 (mean age 51 ± 13 years) male patients with sexual dysfunction was studied.Main Outcome MeasuresSeveral hormonal and biochemical parameters were investigated, along with SIEDY and the MHQ.ResultsHigher prolactin was observed only in patients using SSRIs, whereas no other hormonal difference was found after adjustment for confounders. Use of SSRIs was associated with a twofold risk for patient hypoactive sexual desire and with a higher impairment of reported erectile function. However, no difference in penile blood flow was observed. A very high risk (sevenfold) for delayed ejaculation (DE) was observed in SSRI users. Interestingly, the association with the mild, but not severe, form of DE was observed also in subjects using non-SSRI antidepressants (3.35 [1.48–7.59]; P < 0.005). Different life stressors and relational parameters were also associated with SSRI use. SSRI users reported less enjoyment with masturbation and decreased partner desire and climax. Conversely, a lack of significant association was observed among BDZ or non-SSRI antidepressant users and all the aforementioned life-stressors and relational parameters.ConclusionsSSRIs can negatively affect all the steps of the male sexual response cycle (desire–arousal–excitement–orgasm). SSRI-associated sexual dysfunction has a deleterious effect on both auto- and couple-erotic performances. Conversely, other antidepressants and BDZ are less often associated with sexual impairment. Corona G, Ricca V, Bandini E, Mannucci E, Lotti F, Boddi V, Rastrelli G, Sforza A, Faravelli C, Forti G, and Maggi M. Selective serotonin reuptake inhibitor-induced sexual dysfunction. J Sex Med 2009;6:1259–1269.     

Impact of infertility and infertility treatments on quality of life and levels of anxiety and depression in women undergoing in vitro fertilization

Abstract

This study aims to evaluate levels of anxiety and depression in women, correlated with infertility per se and with infertility treatments, highlighting predictors of higher levels of distress. Two validated standardized questionnaires, the Hospital Anxiety and Depression Scale (HADS) and the Fertility Quality of Life (FertiQoL), were administered to 89 women both before their first cycle of infertility treatment and again at the end of the ovarian stimulation for in vitro fertilization (IVF). Women's levels of anxiety were significantly higher before the treatment than during the treatment itself. Stratifying the women in three groups based on principal cause of infertility (male infertility, female infertility, or both male and female), we found significantly higher levels of anxiety and general distress in patients under treatment for female infertility. Higher anxiety levels in our sample before the treatment are probably an effect of not knowing what they are expected to do to solve their problem. Moreover, when the cause of infertility is exclusively female, women experience higher levels of anxiety and general distress both before and during the treatment, probably correlated to a sense of guilt. These data help the treating physician to better counsel patients and to provide a more focused psychological support.     

Use of DDDRP pacing device in prevention and treatment of tachy-brady syndrome after Mustard procedure

A 13-year-old male patient, who underwent Mustard operation for a very complex congenital heart disease (CHD), after palliation presented a decrease of the sinus node function, developing a tachy-brady syndrome and a mild dysfunction of atrioventricular (AV) conduction. He was successfully treated using a DDDRP pacemaker, which ensured a suitable atrial rhythm and was able to interrupt supraventricular tachycardia episodes. Until now, hospitalization related to episodes of heart failure or symptomatic arrhythmia, has not been necessary.     

Liposome/water lipophilicity: methods, information content, and pharmaceutical applications

This review discusses liposome/water lipophilicity in terms of the structure of liposomes, experimental methods, and information content. In a first part, the structural properties of the hydrophobic core and polar surface of liposomes are examined in the light of potential interactions with solute molecules. Particular emphasis is placed on the physicochemical properties of polar headgroups of lipids in liposomes. A second part is dedicated to three useful methods to study liposome/water partitioning, namely potentiometry, equilibrium dialysis, and (1)H-NMR relaxation rates. In each case, the principle and limitations of the method are discussed. The next part presents the structural information encoded in liposome/water lipophilicity, in other words the solutes' structural and physicochemical properties that determine their behavior and hence their partitioning in such systems. This presentation is based on a comparison between isotropic (i.e., solvent/water) and anisotropic (e.g., liposome/water) systems. An important factor to be considered is whether the anisotropic lipid phase is ionized or not. Three examples taken from the authors' laboratories are discussed to illustrate the factors or combinations thereof that govern liposome/water lipophilicity, namely (a) hydrophobic interactions alone, (b) hydrophobic and polar interactions, and (c) conformational effects plus hydrophobic and ionic interactions. The next part presents two studies taken from the field of QSAR to exemplify the use of liposome/water lipophilicity in structure-disposition and structure-activity relationships. In the conclusion, we summarize the interests and limitations of this technology and point to promising developments.     

Involvement of somatostatin in breathing control before and after birth, and in perinatal and infant sudden unexplained death

The distribution of the somatostatin was studied by immunohistochemistry on serial sections of the 56 brain stems from subjects aged from 30 gestational weeks to 12 postnatal months, dying of both known and unknown causes. The unexplained deaths included 13 sudden intrauterine deaths, 4 sudden neonatal deaths and 24 sudden infant deaths. We observed intense somatostatin positivity in the cell bodies and fibres of many brainstem nuclei prevalently involved in the respiratory activity (parabrachial/K?lliker-Fuse complex, locus coeruleus, hypoglossus nucleus, dorsal vagus motor nucleus, tractus solitarii nucleus, ambiguus nucleus, and reticular formation) in stillbirths. Only in 8 foetuses with unexplained death the hypoglossus nucleus was somatostatin-negative. In the postnatal deaths, the immunopositivity was prevalently limited to the ventrolateral and ventral subnuclei of the tractus solitarii nucleus. In 13 sudden infant death victims and in one case of death due to pneumonia, somatostatin-positivity was also present in the hypoglossus nucleus. We concluded that: 1) the somatostatin is an important foetal breathing-inhibitor, but it becomes important for the physiological control of respiration immediately after delivery; 2) functional alterations of the hypoglossal nucleus can occur in both sudden perinatal and infant deaths and contribute to the induction of both fatal breathing movements in foetuses and abnormal ventilatory control in infants leading to irreversible apneic phenomena.     

Angioneurotic edema of the upper airways and antihypertensive therapy

Angioneurotic edema is a non-pitting edema which is usually limited to the skin and the mucous membranes of the face and upper aerodigestive tract. The risk of acute upper airway obstruction makes angioneurotic edema a concern for emergency room physicians, internists and otolaryngologists because prompt recognition of the condition and immediate institution of therapy is essential for proper airway management. Angiotensin-converting enzyme (ACE) inhibitors have recently been associated with angioneurotic edema, the probable link being the reduction in angiotensin II and the potentiation of bradykinin, resulting in vasodilatation, increased vascular permeability and angioedema. We report four cases of acquired angioneurotic edema, which were probably related to ACE inhibitor use. These cases are discussed, including a review of the literature, methods of diagnosis, pathophysiology and treatment of angioedema. Care should be taken when antihypertensive ACE inhibitor treatments are started and patients should be warned of the potential risk of angioneurotic edema.