Rossella Cannarella

Androgen excess and metabolic disorders in women with PCOS: beyond the body mass index

BackgroundInsulin resistance is a common feature among women with polycystic ovary syndrome (PCOS), especially in those patients with hyperandrogenism and chronic anovulation. PCOS women are at risk for developing metabolic syndrome, impaired glucose tolerance and type II diabetes mellitus (DM II).ObjectiveThe aim of this review is to explore the existing knowledge of the interplay between androgen excess, pancreatic β-cell function, non-alcoholic fatty liver disease (NAFLD), intra-abdominal and subcutaneous (SC) abdominal adipocytes in PCOS, providing a better comprehension of the molecular mechanisms of diabetologic interest.MethodsA comprehensive MEDLINE® search was performed using relevant key terms for PCOS and DM II.ResultsInsulin-induced hyperandrogenism could impair pancreatic β-cell function, the SC abdominal adipocytes’ lipid storage capacity, leading to intra-abdominal adipocyte hypertrophy and lipotoxicity, which in turn promotes insulin resistance, and could enhance NAFLD. Fetal hyperandrogenism exposure prompts to metabolic disorders. Treatment with flutamide showed to partially reverse insulin resistance.ConclusionsMetabolic impairment seems not to be dependent only on the total fat mass content and body weight in women with PCOS and might be ascribed to the androgen excess.

Effects of the insulin-like growth factor system on testicular differentiation and function: a review of the literature

We recently described the occurrence of cryptorchidism, oligoasthenoteratozoospermia, and genital abnormalities in patients with distal 15q chromosome structural abnormalities. This observation brought us to hypothesize that insulin‐like growth factor (IGF) receptor (IGF1R), mapping on the 15q 26.3 chromosomal band, may be involved in testicular function. To further evaluate this topic, we reviewed in vitro and in vivo studies exploring the role of the IGF system [IGF1, IGF2, IGF1R, insulin receptor substrates (IRS)] at the testicular level both in animals and in humans. In animals, IGF1/IGF1R has been found to be involved in testicular development during embryogenesis, in Sertoli cell (SC) proliferation, and in germ cell (GS) proliferation and differentiation. Interestingly, IGF1R seems to mediate follicle‐stimulating hormone (FSH) effects through the PI3K/AKT pathway. In humans, IGF1 directly increases testicular volume. The molecular pathways responsible for testicular differentiation and IGF1/IGF1R signaling are highly conserved among species; therefore, the IGF system may be involved in FSH signaling also in humans. We suggest a possible molecular pathway occurring in human SCs, which involves both IGF1 and FSH through the PI3K/AKT pathway. The acknowledgment of an IGF1 mediation of the FSH‐induced effects may open new ways for a targeted therapy in idiopathic non‐FSH‐responder oligoasthenoteratozoospermia.

Consequences on aging process and human wellness of generation of nitrogen and oxygen species during strenuous exercise

Abstract Impairment of antioxidant defense system and increase in metabolic rate and production of reactive oxygen species have been demonstrated in strenuous exercise. Both at rest and during contractile activity, skeletal muscle generates a very complex set of reactive nitrogen and oxygen species; the main generated are superoxide and nitric oxide. The nature of the contractile activity influences the pattern and the magnitude of this reactive oxygen and nitrogen species (ROS) generation. The intracellular pro-oxidant/antioxidant homeostasis undergoes alteration owing to strenuous exercise and the major identified sources of intracellular free radical generation during physical activity are the mitochondrial electron transport chain, polymorphoneutrophil, and xanthine oxidase. Reactive oxygen species increased tissue susceptibility to oxidative damage and pose a serious threat to the cellular antioxidant defense system. The possible dangerous consequences of the aging process and human wellness are emphasized in this review.

Lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction: from physiology to clinical aspects

Abstract Erectile dysfunction, prostatic hyperplasia and lower urinary tract symptoms hare important pathogenetic links. Endothelial dysfunction and hormonal alterations represent the main aspects. The present article examines the anatomical, physiological, and pathophysiological characteristics of this association, finalizing the text to an interpretation of the clinical management of these patients based on these functional considerations.

Epidemiology and risk factors of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction

Abstract Benign prostatic hyperplasia (BPH) is very common in aging men and causes lower urinary tract symptoms (LUTS), which decrease health-related quality of life. A number of evidence suggests that other than ageing, modifiable factors, such as increasing prostate volume, obesity, diet, dyslipidemia, hormonal imbalance, hypertension, metabolic syndrome, alcohol, and smoking, also contribute to the development of BPH and/or LUTS. More recently, erectile dysfunction (ED) has been linked to LUTS/BPH as a part of this syndrome, suggesting that patients with BPH or LUTS easily develop ED, and that LUTS/BPH symptoms often coexist with ED. This article focuses on the epidemiology and risk factors of the combined phenotype LUTS/BPH – ED.

Anejaculation in a patient with Charcot–Marie–Tooth

neurons from the hypogastric nerve innervate vas deferens, seminal vesicles, and prostate and the bladder neck. Noradrenaline release increases the intraluminal pressure of such districts, carrying spermatozoa into the posterior urethra.3 Previous authors suggested that anejaculation could be due to the psychological factors in these patients.1 However, we showed the presence of seminal vesicles atony in a patient with CMT 1B carrying the MPZ Ser78Leu mutation. In addition, neurogenic bladder has been described in CMT patients with MPZ mutations4,5 and a prevalent parasympathetic nervous system involvement has been observed, especially in patients with the MPZ Thr124Met mutation.4 Since ejaculation occurs after noradrenaline release in postganglion synaptic space in healthy men, we speculate that MPZ mutations, by affecting the ANS and the balance between sympathetic and parasympathetic signals, may negatively affect seminal vesicles emptying, leading to anejaculation. Consistent with this hypothesis, infertility has never been described in CMT patients. Thus, anejaculation may selectively regard some CMT types. However, further studies are needed to timely estimate the prevalence of anejaculation in patients with CMT and its association, if any, with CMT types. The presence of urogenital and sexual dysfunction has been already shown in women with CMT.5,6 Lower urinary tract dysfunction (LUTS),7 Dear Editor, The occurrence of delayed ejaculation or anejaculation has been previously suggested in patients with Charcot–Marie–Tooth (CMT) syndrome.1 Despite this, such disorder is rarely investigated and may be underestimated in patients with this disease. We report the case of a 20-year-old men with CMT 1B due to the presence of a punctiform mutation in the exon 2 of the myelin protein zero (MPZ) gene (1q23.3) (Ser78Leu), complaining for life-long anejaculation. He inherited this mutation from the mother and it has also been detected in his grandmother. No other components of his family were positive at the genetic testing. This study was approved by the Intradivisional Ethics Committee of the Andrology Section, and the informed consent was provided by the patient for the publication of his clinical data. The patient was able to achieve the orgasm. At the andrological examination, the testicular volume was of 10 ml bilaterally, and the epididymis was of normal shape and consistency. The vas deferens was present bilaterally. Secondary sexual characters were normally represented. The hormonal profile (luteinizing hormone, follicle-stimulating hormone, prolactin, and total testosterone) did not reveal any abnormality. At the urine examination, performed for two different occasions after orgasm, no spermatozoa were found. The prostate-vesicular ultrasound examination showed, at baseline, a normal prostate volume; the ampulla of the ductus deferens was present and not dilated bilaterally. The seminal vesicles were not dilated; the fundus anteroposterior diameter (APD) of the right seminal vesicle was 10 mm, and 11 mm was that of the left seminal vesicle. In both seminal vesicles, the fundus APD was remeasured after orgasm: on the right seminal vesicle it was 8 mm and on the left one it was 9 mm. The difference between the fundus APD measured at baseline and after orgasm was lower than 3 mm (Figure 1). According to a previous study,2 the ultrasound evaluation was compatible with a bilateral atony of seminal vesicles. The pudendal nerve somatosensory evoked potentials (SEP) showed a dysfunction occurring at the level of the peripheral nerve, while at the level of the spinal cord and the cortex, the examination did not show any abnormality. The patient was able to achieve the erection through masturbation and did not complain about erectile dysfunction (ED). Accordingly, the gland sensitivity, evaluated by penile biothesiometry, did not reveal any abnormality. During ejaculation, the autonomic nervous system (ANS) controls the emission phase in healthy men. Postganglion noradrenergic LETTER TO THE EDITOR

Decreased miRNA expression in Klinefelter syndrome

The widelyvariable phenotypic spectrum and the different severity of symptoms in men with Klinefelter syndrome (KS) suggest a role for epigenetic mediators. Therefore, the aim of this study is to evaluate the possible involvement of miRNAs in the clinical manifestations of KS. To accomplish this, we performed a transcriptome analysis in peripheral blood mononuclear cells (PBMCs) of 10 non-mosaic KS patients, 10 aged-matched healthy men and 10 aged-matched healthy female controls with normal karyotype. After RNA extraction from PBMC and the preparation of RNA libraries, the samples were sequenced using next generation high-throughput sequencing technology. Expression profiling analysis revealed a significant differential expression of 2 miRNAs in KS compared to male controls. In particular, MIR3648 resulted significantly (q-value < 0.0001) down-regulated by −19.084- fold, while MIR3687was strongly down-regulated (q-value < 0.0001) considering KS patients. These results were confirmed by qRT-PCR. The functional analysis of the two transcripts showed that they seem to play a role in breast cancer, hemopoietic abnormalities, immune defects and adipocyte differentiation and fat cell maturation. Therefore, we speculate that both miRNAs may play a role in the immune and metabolic disorders and in the risk of breast cancer development in men with KS.

Reduced Seminal Concentration of CD45pos Cells after Follicle-Stimulating Hormone Treatment in Selected Patients with Idiopathic Oligoasthenoteratozoospermia

The present study evaluated the conventional sperm parameters and the seminal concentration of CD45pos cells (pan-leukocyte marker) of infertile patients with idiopathic oligoasthenoteratozoospermia (OAT). The patients were arbitrarily divided into three groups treated with recombinant follicle-stimulating hormone FSH: α (Group A = 20 patients), recombinant FSH-β (Group B = 20 patients), and highly purified human FSH (Group C = 14 patients). All treated groups achieved a similar improvement of the main sperm parameters (density, progressive motility, and morphology), but only the increase in the percentage of spermatozoa with normal morphology was significant compared to the baseline in all three examined groups. Moreover, all groups had a significant reduction of the seminal concentration of CD45pos cells and of the percentage of immature germ cells. Before and after the treatment, the concentration of CD45pos cells showed a positive linear correlation with the percentage of immature germ cells and a negative correlation with the percentage of spermatozoa with regular morphology. These results demonstrate that treatment with FSH is effective in patients with idiopathic OAT and that there are no significant differences between the different preparations. The novelty of this study is in the significant reduction of the concentration of CD45pos cells observed after the treatment.

Urogenital dysfunction in male patients with Charcot-Marie-Tooth: a systematic review

INTRODUCTION Charcot-Marie-Tooth (CMT) is the most common inherited polyneuropathy. Polyneuropathies are likely to affect the urogenital system. Urogenital dysfunction is rarely investigated and may be underestimated in CMT patients. AIM The aim of the present study was to perform a systematic review of the literature to collect all the available evidence on the presence of urogenital dysfunction and in patients with CMT. METHODS Data sources were MEDLINE, Pubmed, Scopus, and Google Scholar. All types of studies describing the presence of lower urinary tract dysfunction, erectile dysfunction (ED), anejaculation, and other sexual disorders in male patients with CMT were included. RESULTS Among 131 records identified, five articles were included in the qualitative synthesis. Lower urinary tract dysfunction, neurogenic bladder, ED, and other sexual dysfunctions have been reported in patients with CMT. One case of anejaculation has been described. CONCLUSION Urogenital dysfunction occurs in patients with CMT. Therefore, uro-andrologic counseling should be performed in the aging male with CMT. This might positively impact on his quality of life.

Treatment of lower urinary tract symptoms/benign prostatic hyperplasia and erectile dysfunction

Abstract This article summarizes years of challenging research on erectile dysfunction (ED), a condition that has an important social and cultural relevance. Preclinical and clinical research progress has led to new therapeutic approaches to ED in patients with different comorbidities and particularly in those with low urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH). These goals were possible only by combined work of specialists and researchers of different and intertwined medical disciplines. Currently, tadalafil (5 mg/d) is the best choice; other phosphodiesterase-5 inhibitors (PDE5i) are not included among options, despite the growing evidence of therapeutic effects. Different regimens of tadalafil may be prescribed based on patient needs, severity of LUTS/BPH – ED profile, and clinical experience. An integrated approach is necessary to choose for a combined therapy with PDE5i and α-blockers following urological and cardiac counseling in terms of outcomes and adverse effects.