Carlo Foresta

Introduction: Decreased bone mineral density (BMD) in Klinefelter syndrome (KS) is frequent and it has been traditionally related to low testosterone levels. However, low BMD can be observed also in patients with normal testosterone levels and testosterone replacement therapy does not necessarily increase bone mass in these patients. Nothing is known about vitamin D levels and supplementation in KS. In this study we determine vitamin D status and bone mass in KS subjects and compare the efficacy of testosterone therapy and vitamin D supplementation on BMD. Methods: A total of 127 non-mosaic KS patients and 60 age-matched male controls were evaluated with reproductive hormones, 25-hydroxyvitamin D, PTH, and bone densitometry by DEXA. Patients with hypogonadism and/or 25-hydroxyvitamin D deficiency were treated with testosterone-gel 2% and/or calcifediol and re-evaluated after 24 months of treatment. Results: 25-hydroxyvitamin D levels were significantly lower in KS patients with respect to controls, and they had significantly lower lumbar and femoral BMD. The percentage of osteopenia/osteoporosis in subjects with 25-hydroxyvitamin D deficiency was higher with respect to subjects with normal 25-hydroxyvitamin D and was not related to the presence/absence of low testosterone levels. Subjects treated with calcifediol or testosterone+calcifediol had a significant increase in lumbar BMD after treatment. No difference was found in testosterone-treated group. Conclusions: These data highlight that low 25-hydroxyvitamin D levels have a more critical role than low testosterone levels in inducing low BMD in KS subjects. Furthermore, vitamin D supplementation seems to be more effective than testosterone replacement therapy alone in increasing BMD.

To restore testicular functional competence after traumatic avulsion of the scrotum, accompanied by penile decortication, by means of ad hoc surgery and post-surgical medical treatment. A 26 years old patient underwent a on the job perineal trauma that resulted in loss of one testis while the other one was rescued together with the deferential duct. The spared testis was buried in a subcutaneous thigh pocket after creating a tunnel from the inguinal area. Because of post-traumatic ensued hypogonadism, the patient was treated with corticosteroids, phosphodiesterase 5 inhibitors and anti-oxidizing agents. Hypogonadism related clinical findings in terms of oligospermia, erectile dysfunction and alterations of the pituitary- testis axis, with low testosterone levels progressively improved along the post-traumatic months. Preservation of testis vascular supply associated with ad hoc medical therapy restored erectile dysfunction and spermatogenesis, and in the end at 6 months of the trauma the patients was able to regain fatherhood capability. The obtained results demonstrate that an appropriate testis burying in the subcutaneous thigh region, upon traumatic scrotum avulsion, followed by an ad hoc medical therapy may rescue male fertility. This is unlikely to happen in the clinical routine and previous published reports negate restoration of the testis function, that completely vanishes within 1 year of the intervention. Full restoration of testis and penile functions resulted in induction of spontaneous pregnancy in the patient's female partner may occur only if good reconstructive surgery is coupled with an efficient medical therapy.

Obesity and cardiovascular diseases share clinical features such as altered insulin sensitivity, fasting glycemia, lipid and hormonal pattern. Osteocalcin (OCN), traditionally known to be a bone-related marker as Gla-carboxylated protein (cOCN), has recently grown in interest for the protective role, exerted by its undercarboxylated form (ucOCN), in metabolic diseases. Recent studies performed in cohorts of obese patients documented that ucOCN/OCN ratio is negatively correlated to BMI and that both subcutaneous (SAT) and omental (OAT) adipose tissue express OCN and all genes involved in OCN Gla-carboxylation. Moreover both types of adipose tissue are able to release OCN in both its carboxylated and undercarboxylated form. Here we investigated in vitro the effect of androgen stimulation on OCN release by OAT, mainly involved in metabolic disorders. DHT stimulation for 24h was able to significantly increase the release of both ucOCN and cOCN by OAT at concentration of respectively 10-12 to 10-8M and 10-10 to 10-8M. This effect was androgen specific as evidenced by its abrogation in presence of an androgen receptor antagonist (flutamide). Moreover DHT enhanced the ucOCN/OCN ratio in a DHT concentration-dependent manner. We then evaluated 28 normal and 63 overweight-obese male subjects for plasma levels of cOCN, ucOCN, leptin, testosterone (total and free) and estradiol. As expected, we found that free testosterone was negatively correlated with BMI (r = -0.706, P<0.001) whereas, interestingly, ucOCN/OCN ratio was significantly and positively correlated with free-testosterone (r =0.223, P<0.05). In conclusion our data strengthen the protective effect of androgens from metabolic disorders, by adding a new role on the modulation of the relative amount of ucOCN released by the adipose tissue. Nothing to Disclose: LDT, AF, GS, LG, UC, AG, CF

Erectile dysfunction (ED), defined as the inability to achieve and/or maintain an erection sufficiently long for a satisfactory sexual performance or intercourse, is an important and common medical problem. ED is not a life-threatening disorder, but it influences the daily routine, social interactions, well-being and quality of life of the patient. Recent epidemiological data have shown a high prevalence and incidence of ED. The Massachusetts Male Aging Study found that 52% of men between the ages of 40 and 70 years reported ED with 9.6% having mild, 22.2% moderate and 17.2% complete or severe ED. In a large Italian cross-sectional study the overall prevalence of self-reported ED was 12.8% and the frequency of ED increases with age. ED may signal serious underlying and potentially life-threatening diseases, such as diabetes, hypertension, cardiovascular disease, peripheral vascular disease and other neurological and endocrine disorders. Also well documented is the role of some drug groups, certain types of surgery, injuries and the role of risk factors related to lifestyle such as smoking, alcohol consumption and inappropriate dietary habits accompanied by an abnormal serum level of cholesterol. The current availability of effective and safe oral drugs for ED in conjunction with the tremendous media interest in the condition, have resulted in an increasing number of men seeking help for ED. As a consequence, many physicians without background knowledge and clinical experience in the diagnosis of ED are involved in making decisions concerning the evaluation of such patients. The result of this is that some males with ED may undergo little or no evaluation before treatment is initiated and, in such circumstances, the disease causing the symptom (ED) may remain untreated. Baseline diagnostic evaluation for ED can identify the underlying pathological condition or the risk factors associated with ED in 80% of patients. This article reports a sequential approach for the diagnosis of ED that may diagnose reversible causes of ED and also unmask medical conditions that manifest with ED as the first symptom.

Erectile function progressively declines with age, although most old men's erectile rigidity remains adequate for vaginal intercourses. Recently it has been demonstrated that a significant proportion of men over 60 years of age has a biochemical hypogonadism (defined as below the 2.5th percentile for young men). It is generally accepted that erectile response in mammals is regulated by androgens both centrally and peripherically, but in male ageing a casual relationship between androgen levels and erectile function has not been established yet. The present study was designed to evaluate the possible relationships between circulating androgens and sexual activity in a group of healthy old men without erectile dysfunction. Forty men with a mean age of 68 +/- 6 years (range 61-75 years) were recruited among healthy subjects undergoing periodic health screening. The control group consisted of 30 young volunteers with a mean age of 33 +/- 5 years (range 26-40 years). These subjects had good general health and stable relationship with at least one successful intercourse for week. All subjects performed: 1) hormonal assessment (total testosterone, free testosterone, DHT, FSH and LH); 2) nocturnal penile tumescence monitoring during two consecutive nights. The findings of this study show a significant decrease in frequency, duration and degree of nocturnal erectile episodes in old men with respect to those observed in young controls. The alteration of these parameters was more evident in old subject showing a reduction of testosterone plasma levels. In hypotestosteronemic subjects DHT treatment significantly improved nocturnal penile tumescence parameters even if these still differed from those of controls (p<0.001). On the basis of these observations we hypothesize that hypoandrogenism in old men, also in presence of normal sexual activity, may influence locally the erectile mechanisms. However hypoandrogenism, associated to other conditions negatively influencing the erectile activity, may be an important co-factor in the induction of erectile dysfunction in aging.

The Y chromosome has a fundamental role in sex determination and regulation of spermatogenesis. Three regions (designated as AZFa, b, and c) on the long arm of this chromosome exist, deletions of which result in severe damage to spermatogenesis with azoospermia or severe oligozoospermia. Recent progresses in molecular biology and extraordinary development of assisted reproduction techniques contributed to the research on this chromosome and the genes involved in spermatogenesis. About 10-15% of subjects affected by azoospermia or severe oligozoospermia carry a deletion in one or more AZF regions, 60% of which involves AZFc. The genes responsible for the testicular phenotype observed in these subjects are DBY and USP9Y for AZFa, RBMY1 for AZFb, and DAZ for AZFc. In this article, the current knowledge on biology and genetics of the Y chromosome are reported with particular interest to deletions found in infertile subjects. Furthermore, the more recent advances on DAZ gene and its role in spermatogenesis and male infertility are discussed.

OBJECTIVE: The DAZ (deleted in azoospermia) gene family on the Y chromosome long arm is the major candidate for the AZFc (azoospermia factor c) phenotype of male infertility and it is expressed only in germ cells. The aim of the study was to assess Sertoli cell function in subjects with AZFc deletions. DESIGN: Case-control, prospective study. METHODS: We have studied six severely oligozoospermic subjects with AZFc-DAZ deletions, and looked whether they responded in terms of inhibin B production to a 1 month FSH treatment. These patients were compared with three groups of patients affected by different spermatogenic alterations not related to deletions on the Y chromosome. RESULTS: Although affected by severe testiculopathy, patients with AZFc-DAZ deletions had only slightly elevated FSH, and normal inhibin B plasma concentrations. Inhibin B responded normally during FSH treatment, supporting the hypothesis that Sertoli cells are not altered. On the contrary, other severe testiculopathies not related to Y chromosome deletions showed high FSH and low inhibin B concentrations, with no response to FSH treatment. In these cases the cause of the spermatogenic defect probably damaged both germ and Sertoli cells. Finally, idiopathic patients with a hormonal status similar to Y-deleted patients (slightly elevated FSH and normal inhibin B concentrations) did not respond to FSH treatment, suggesting that Sertoli cells were already at their maximal functional capability. CONCLUSIONS: These data confirm that Sertoli cell function is not damaged in patients with AZFc-DAZ deletions and that the strong reduction of germ cells does not affect the FSH-inhibin B feedback loop.

Research on genetic causes of male and female infertility rapidly expanded in the last years, following the development of in vitro fertilising techniques. Genetic tests are now available to explore the cause of the infertility and assess the risk of a given couple to transmit its genetic characteristics. This allows at-risk couples to take an informed decision when electing for a medically assisted reproduction. It also allows the professionals to offer a prenatal diagnosis when appropriate. Thus, the genetic work-up of the infertile couple has become good practice for an appropriate diagnosis, treatment and prognostic assessment. The lack of national or international rules for the genetic approach to the infertile couple, prompted the Italian community of professionals in the field of reproductive medicine to join and set up guidelines for the genetic diagnosis of male and female infertility. The group of clinical and research experts is representative of 12 national scientific societies and was supported by external experts from four international societies. We examine the clinically relevant genetic causes of male and female infertility and suggest the category of patients for which each genetic test is recommended or optional, both for an accurate diagnosis and prior to ART.