Testosterone treatment in male patients with Klinefelter syndrome: a systematic review and meta-analysis.

PURPOSE: Low testosterone (T) in Klinefelter's syndrome (KS) can contribute to typical features of the syndrome such as reduced bone mineral density, obesity, metabolic disturbances and increased cardiovascular risk. The aim of the present study is to review and meta-analyze all available information regarding possible differences in metabolic and bone homeostasis profile between T treated (TRT) or untreated KS and age-matched controls. METHODS: We conducted a random effect meta-analysis considering all the available data from observational or randomized controlled studies comparing TRT-treated and untreated KS and age-matched controls. Data were derived from an extensive MEDLINE, Embase, and Cochrane search. RESULTS: Out of 799 retrieved articles, 21 observational and 22 interventional studies were included in the study. Retrieved trials included 1144 KS subjects and 1284 healthy controls. Not-treated KS patients showed worse metabolic profiles (including higher fasting glycemia and HOMA index as well as reduced HDL-cholesterol and higher LDL-cholesterol) and body composition (higher body mass index and waist circumference) and reduced bone mineral density (BMD) when compared to age-matched controls. TRT in hypogonadal KS subjects was able to improve body composition and BMD at spinal levels but it was ineffective in ameliorating lipid and glycemic profile. Accordingly, TRT-treated KS subjects still present worse metabolic parameters when compared to age-matched controls. CONCLUSION: TRT outcomes observed in KS regarding BMD, body composition and glyco-metabolic control, are similar to those observed in male with hypogonadism not related to KS. Moreover, body composition and BMD are better in treated than untreated hypogonadal KS. Larger and longer randomized placebo-controlled trials are advisable to better confirm the present data, mainly derived from observational studies.

SARS-CoV-2 infection, male fertility and sperm cryopreservation: a position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) (Società Italiana di Andrologia e Medicina della Sessualità).

PURPOSE: The recent pandemic of severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS-CoV-2) has raised several concerns in reproductive medicine. The aim of this review is to summarize available evidence providing an official position statement of the Italian Society of Andrology and Sexual Medicine (SIAMS) METHODS: A comprehensive Pubmed, Web of Science, Embase, Medline and Cochrane library search was performed. Due to the limited evidence and the lack of studies, it was not possible to formulate recommendations according to the Oxford 2011 Levels of Evidence criteria. RESULTS: Several molecular characteristics of the SARS-CoV-2 can justify the presence of virus within the testis and possible alterations of spermatogenesis and endocrine function. Orchitis has been reported as a possible complication of SARS-CoV infection, but similar findings have not been reported for SARS-CoV-2. Alternatively, the orchitis could be the result of a vasculitis as COVID-19 has been associated with abnormalities in coagulation and the segmental vascularization of the testis could account for an orchitis-like syndrome. Finally, available data do not support the presence of SARS-CoV-2 in plasma seminal fluid of infected subjects. CONCLUSION: Data derived from other SARS-CoV infections suggest that in patients recovered from COVID-19, especially for those in reproductive age, andrological consultation and evaluation of gonadal function including semen analysis should be suggested. Studies in larger cohorts of currently infected subjects are warranted to confirm (or exclude) the presence of risks for male gametes that are destined either for cryopreservation in liquid nitrogen or for assisted reproduction techniques.

Endocrine and psychological aspects of sexual dysfunction in Klinefelter patients.

Klinefelter syndrome is a frequent cause of hypogonadism, but despite hundreds of publications on different aspects of Klinefelter syndrome, only a few studies dealt with sexual dysfunction. In particular, testosterone is critical for various aspects of sexual response, but its role on sexuality in Klinefelter syndrome patients is debatable and no studies have evaluated the efficacy of testosterone treatment on sexual dysfunction in these subjects. Furthermore, the impact of psychological and relational aspects on sexual function of Klinefelter syndrome subjects is poorly defined. In this study, we aimed to determine the presence and type of sexual dysfunctions in Klinefelter syndrome subjects; to correlate them with testosterone levels and psychosexological and relational domains; and to evaluate the effects of testosterone therapy. We studied 62 non-mosaic naïve Klinefelter syndrome patients and 60 age-matched controls by means of medical history, psychosexological history, 15-item International Index of Erectile Function questionnaire, endocrine assessment, and dynamic penile color Doppler ultrasound. Twenty-five hypogonadal Klinefelter syndrome patients were studied after 6 months of testosterone replacement therapy. Klinefelter syndrome subjects have reduced 15-item International Index of Erectile Function scores regarding sexual desire, intercourse satisfaction, and overall satisfaction with respect to controls, and these aspects were significantly associated with testosterone levels. Klinefelter syndrome subjects had also higher prevalence of erectile dysfunction, but no relation with testosterone levels was evident. A high prevalence of a range of psychological disturbances was present in Klinefelter syndrome subjects with erectile dysfunction with respect to those without erectile dysfunction. No statistical difference in the prevalence of premature and delayed ejaculation was observed between Klinefelter syndrome and control subjects. Testosterone replacement therapy improved sexual desire, intercourse satisfaction, and overall satisfaction scores, but had no effect on erectile function. Penile color Doppler ultrasound was normal in all subjects. This study shows that sexual dysfunction in Klinefelter syndrome is multifactorial and related only in part to hypogonadism and largely to psychological disturbances. Evaluation and therapy of sexual dysfunction should include a combined andrological and psychosexological approach.

Predictors and clinical consequences of starting androgen therapy in men with low testosterone: results from the SIAMO-NOI registry.

PURPOSE: Management of late onset hypogonadism (LOH) is not homogenous. The aim of the study is to observe the management of patients with low testosterone (T) in highly specialized Italian centres. METHODS: The SIAMO-NOI is an observational longitudinal disease registry for the evaluation of the clinical management of patients with low T levels (total T < 12 nmol/L, calculated free T < 225 pmol/l or already in treatment) in 15 Italian centers members of the Italian Society for Andrology and Sexual Medicine (SIAMS). Clinical and biochemical data were collected for four visits during 12 months of observation. RESULTS: 432 patients (mean age 50.9 ± 14.9 years) were enrolled. Of them, 247 men were receiving androgen therapy, whereas 145 were naive. After the first visit (V0), 80 men started androgen therapy, whereas 55 remained untreated during the entire observation. Younger age [odds ratio (OR) 0.57 (0.35-0.92)], total T < 8 nmol/l [OR 4.69 (1.59-13.81)], complaining at least one sexual symptom [OR 11.55 (2.01-66.35)] and reporting more severe lower urinary tract symptoms [OR 1.27 (1.01-1.60)] predicted starting an androgen therapy. Sixty-four men started therapy immediately after V0 and maintained it until the observation end. When compared to V0, they reported an increase in all the domains of the International Index of Erectile Function-15 (IIEF-15), in the sexual and physical subdomains of the Aging Male Scale as well as in the International Prostate Symptom Score. Conversely, the untreated group reported a significant improvement, although lower than the treated group, only in the erectile function domain of the IIEF-15. CONCLUSIONS: Management of LOH in SIAMS centres is in line with the international guidelines and the newest knowledge about the role of T on prostate health. Androgen therapy is associated with an improvement in all the aspects of sexual life and in the perception of physical strength.

The Klinefelter syndrome is associated with high recurrence of copy number variations on the X chromosome with a potential role in the clinical phenotype.

The Klinefelter syndrome (KS) is the most frequent sex chromosomal disorder in males, characterized by at least one supernumerary X chromosome (most frequent karyotype 47,XXY). This syndrome presents with a broad range of phenotypes. The common characteristics include small testes and infertility, but KS subjects are at increased risk of hypogonadism, cognitive dysfunction, obesity, diabetes, metabolic syndrome, osteoporosis, and autoimmune disorders, which are present in variable proportion. Although part of the clinical variability might be linked to a different degree of testicular function observed in KS patients, genetic mechanisms of the supernumerary X chromosome might contribute. Gene-dosage effects and parental origin of the supernumerary X chromosome have been suggested to this regard. No study has been performed analyzing the genetic constitution of the X chromosome in terms of copy number variations (CNVs) and their possible involvement in phenotype of KS. To this aim, we performed a SNP arrays analysis on 94 KS and 85 controls. We found that KS subjects have more frequently than controls X-linked CNVs (39/94, [41.5%] with respect to 12/42, [28.6%] of females, and 8/43, [18.6%] of males, p < 0.01). The number of X-linked CNVs in KS patients was 4.58 ± 1.92 CNVs/subject, significantly higher with respect to that found in control females (1.50 ± 1.29 CNVs/subject) and males (1.14 ± 0.37 CNVs/subject). Importantly, 94.4% X-linked CNVs in KS subjects were duplications, higher with respect to control males (50.0%, p < 0.001) and females (83.3%, p = 0.1). Half of the X-linked CNVs fell within regions encompassing genes and most of them (90%) included genes escaping X-inactivation in the regions of X-Y homology, particularly in the pseudoautosomal region 1 (PAR1) and Xq21.31. This study described for the first time the genetic properties of the X chromosome in KS and suggests that X-linked CNVs (especially duplications) might contribute to the clinical phenotype.

Role of vitamin D levels and vitamin D supplementation on bone mineral density in Klinefelter syndrome.

UNLABELLED: This manuscript describes the role of low vitamin D in bone metabolism of Klinefelter subjects. Low vitamin D is frequent in this condition and seems to be more important than testosterone in inducing low bone mineral density (BMD) and osteoporosis. Supplementation with vitamin D restores BMD after 2 years of treatment, whereas testosterone alone seems to be ineffective. INTRODUCTION: Decreased bone mineral density (BMD) in Klinefelter syndrome (KS) is frequent, and it has been traditionally related to low testosterone (T) levels. However, low BMD can be observed also in patients with normal T levels and T 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 T 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 dual-energy X-ray absorptiometry (DEXA). Patients with hypogonadism and/or 25-hydroxyvitamin D deficiency were treated with T-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 T levels. Subjects treated with calcifediol or T + calcifediol had a significant increase in lumbar BMD after treatment. No difference was found in T-treated group. CONCLUSIONS: These data highlight that low 25-hydroxyvitamin D levels seem to have a more critical role than low T levels in inducing low BMD in KS subjects. Furthermore, vitamin D supplementation seems to be more effective than T replacement therapy alone in increasing BMD.

Prostate volume and growth during testosterone replacement therapy is related to visceral obesity in Klinefelter syndrome.

OBJECTIVE: Klinefelter syndrome (KS) is a chromosomal alteration characterized by increased risk of metabolic syndrome, mainly caused by visceral obesity. In the last years, obesity has been studied as a potential risk factor for prostate disease and recently a link has been demonstrated between visceral adiposity with prostate volume. The aim of this study was to analyze the relationship between obesity and prostate volume and growth during testosterone therapy in KS subjects. DESIGN AND METHODS: We evaluated reproductive hormones, metabolic parameters, anthropometric measures, PSA, and prostate volume in 121 naïve non-mosaic KS patients and 60 age-matched healthy male controls. Fifty-six KS hypogonadic subjects were treated with testosterone-gel 2% and reevaluated after 18 months of treatment. RESULTS: Prostate volume in KS was positively related to waist circumference (WC). The KS group with WC ≥94 cm had significantly higher prostate volume, BMI, insulin plasma levels, homeostasis model assessment index, total cholesterol, triglycerides, and glycemia with respect to the KS group with WC <94 cm. After testosterone replacement therapy, only hypogonadic KS men with WC ≥94 cm had a statistically significant increase in prostate volume. Furthermore, in untreated KS subjects, prostate volume showed a statistically significant increase after 18 months of follow-up only in subjects with WC ≥94 cm. CONCLUSIONS: This study showed that visceral obesity, insulin resistance, and lipid and glucose metabolism alterations are associated with prostate volume and growth during testosterone replacement therapy in KS, independently from androgen or estrogen levels. These latter findings might provide the basis for a better management and follow-up of KS subjects.

Altered bone status in unilateral testicular cancer survivors: Role of CYP2R1 and its luteinizing hormone-dependency.

BACKGROUND: Recent data suggest a potential role of testis in vitamin D activation, where Leydig cells could represent key players in this process since they express the highest amount of CYP2R1, a key enzyme involved in vitamin D 25 hydroxylation. AIM: To evaluate bone status in unilateral orchiectomy and to assess in vivo and in vitro LH-dependency of Vitamin D 25 hydroxylation. SUBJECTS AND METHODS: 125 normotestosteronemic patients with testicular cancer (TC), featured by unilateral orchiectomy and 41 age-matched healthy male controls were studied in the Center for Human Reproduction Pathology at the University of Padova. To evaluate LH-dependency of Vitamin D 25 hydroxylation in vitro, Leydig cell cultures were stimulated with hCG and assessed for CYP2R1 expression, whereas in vivo 10 hypogonadotropic hypogonadal (HH) patients were evaluated before and after treatment with gonadotropins for bone metabolism markers. Hormonal pattern and bone metabolism markers were measured in all subjects, whereas 105 patients and 41 controls underwent bone densitometry by DEXA. RESULTS: In TC patients 25-hydroxyvitamin D levels were significantly lower compared to controls. Furthermore, 23.8% of patients with TC displayed low bone density (Z-score <-2 SD). None of the 41 control subjects showed any significant alteration of BMD. In vitro and in vivo studies revealed that CYP2R1 expression in Leydig cells appeared to be hCG dependent. CONCLUSION: Our data show an association between TC and alteration of the bone status, despite unvaried androgen and estrogen levels, suggesting the evaluation of bone status and possible vitamin D deficiency in TC survivors.

Reduced artery diameters in Klinefelter syndrome.

Various epidemiological studies in relatively large cohorts of patients with Klinefelter syndrome (KS) described the increased morbidity and mortality in these subjects. Our aim was to study the structure and function of arteries in different districts to investigate in these subjects possible alterations. A total of 92 patients having non-mosaic KS, diagnosed in Centre for Human Reproduction Pathology at the University of Padova, and 50 age-matched healthy male controls were studied. Klinefelter syndrome subjects and controls evaluation included complete medical history, physical examination, measurement of concentrations of the reproductive hormones, lipidic and glycidic metabolism, AR function and sensitivity, ultrasound examinations (diameters, carotid intima-media thickness and brachial flow-mediated dilation) of brachial, common carotid and common femoral artery and abdominal aorta. Klinefelter syndrome patients showed significantly reduced artery diameters in all districts evaluated. On the contrary no statistically significant difference was found in cIMT and brachial FMD values between KS patients and controls. Furthermore, we found no statistically significant correlation of artery diameters with reproductive hormones, metabolic parameters, anthropometric measures and weighted CAG repeats. To our knowledge, this is the first study finding a reduced artery diameter in several districts in KS patients compared with that of normal male subjects and overlapping to that of female subjects. We have not an explanation for this phenomenon, even if a possible involvement of genes controlling the development of vascular system might be hypothesized, and further research is required to verify this hypothesis.

Effects of endogenous FSH on normal human spermatogenesis in adults.

Unilateral orchiectomy (UO) in adult bonnet monkeys and boars elicits a compensatory increase in size and sperm production of the remaining testis. The objective of this study was to investigate whether a similar effect is evident also in humans. We prospectively studied 50 patients from October 2003 to December 2005 who underwent UO for seminomatous tumour, with sperm concentration >20 × 10(6) /mL or total sperm count >40 × 10(6) at diagnosis and without elevation of serum tumour markers. Patients were followed-up with surveillance and they were studied at the time of diagnosis of testicular cancer (T(-1) ), 1 month after unilateral orchiectomy (T(0) ) and yearly for 3 years (T(1) , T(2) , T(3) ) with semen analysis, measurement of plasma levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), inhibin B, total testosterone, and oestradiol and ultrasonographic scanning of the remaining testis. A decline in circulating inhibin B and an increase in FSH levels were evident 1 month after UO. The elevation of FSH was maintained up to 3 years and was associated with a significant increase in testicular volume of 19 and 30%, 2 and 3 years after UO respectively. Although patients had normozoospermia at the time of diagnosis of testicular cancer, they showed a statistically significant increase in total sperm count at T(2) and T(3) with respect to T(-1) and T(0.) In conclusion, we showed that in humans, the testes are not normally operating at their maximal potential in terms of spermatogenesis. Therefore, in physiological situations, FSH secretion is insufficient to stimulate spermatogenesis to its ceiling. A sustained endogenous increase in FSH secretion might drive human testes towards their maximal function.

The response to FSH treatment in oligozoospermic men depends on FSH receptor gene polymorphisms.

In the last years, follice-stimulating hormone (FSH) receptor (FSHR) gene polymorphisms have been studied as potential risk factors for spermatogenetic failure. In this study, we have evaluated the response of FSH treatment in terms of sperm production on the basis of Ala307Thr-Asn680Ser polymorphisms in the FSHR gene in a group of oligozoospermic subjects with hypospermatogenesis and normal FSH levels. Patients were randomized into two groups: 70 treated with recombinant FSH (150 IU thrice per week for 3months) and 35 without treatment. After 3months of treatment, we observed significant increase in total sperm count, sperm concentration, forward motility, percentage of normal morphology forms and total motile sperm. When 70 treated subjects were subdivided based on FSHR genotype, only subjects with at least one serine in position 680 showed a statistically significant increase in these sperm parameters, whereas subjects with homozygote Thr307-Asn680 showed no difference in any seminal parameters evaluated. Non-treated subjects showed no differences in any parameter evaluated. This study suggests that the analysis of this gene represents a valid pharmacogenetic approach to the treatment of male infertility, confirming also the importance of strict criteria for the selection of patients to be treated with FSH.

Increased osteocalcin-positive endothelial progenitor cells in hypogonadal male patients.

OBJECTIVE: Endothelial dysfunction is considered a key factor in the development of cardiovascular diseases. Endothelial regeneration is necessary for the maintenance of endothelial function and circulating endothelial progenitor cells (EPC) participate of it in both direct and indirect manner. The molecular phenotype of EPC is not univocally defined and recent studies identified an osteocalcin (OCN)-positive (EPC-OCN+) subpopulation of EPC highly correlated with atherosclerosis progression. AIM: Considering that hypogonadism is a risk factor for cardiovascular diseases and atherosclerosis, we investigated the circulating levels of EPC-OCN+ in hypogonadal patients. SUBJECTS AND METHODS: Ten hypogonadotropic hypogonadal (HH) male patients and 30 healthy eugonadal men were evaluated for clinical status and hormonal levels. Circulating levels of CD34+/CD133+/kinase insert domain-receptor+ EPC and EPC-OCN+ were also determined by flow cytometry. RESULTS: Compared to controls, HH patients displayed lower FSH, LH, estradiol, testosterone, and EPC levels. On the contrary, EPC-OCN+ were significantly increased. CONCLUSIONS: The observed association of low levels of circulating EPC and increased values of EPC-OCN+ sub-population in hypogonadal men strengthens the significance of hypogonadism as cardiovascular risk factor.

Endothelial progenitor cells as a new cardiovascular risk factor in Klinefelter's syndrome.

Klinefelter syndrome (KS) is associated with a significant reduced life expectancy (2.1 years) including greater mortality from cardiovascular diseases. Underlying causes that may involve low levels of testosterone as well as the extra X chromosome are not fully understood. Low testosterone may have a direct affect on vascular tissue or act indirectly via metabolic effects. Testosterone levels may act genomically on cardiac function via the androgen receptor (AR) or non-genomically. Recently, it has been demonstrated that a reduced number of circulating endothelial progenitor cells (EPCs) is an independent predictor of morbidity and mortality from cardiovascular diseases. Because EPCs have never been studied in KS, we evaluated the number of circulating EPCs in 68 adult 47,XXY Klinefelter men and 46 healthy males. Patients and controls were divided into two groups, according to the absence or presence of cardiovascular risk factors (CRFs). Controls without CRFs had significantly higher levels of EPCs than controls with CRFs; on the contrary, KS patients without CRFs had EPCs levels similar to KS men with risk factors and significantly lower with respect to controls without CRFs. The number of EPCs in patients with hypogonadism was not different from that of those with normal testosterone levels. Twenty-two hypogonadal patients were re-evaluated after 6 months of androgen therapy, but we did not observe any modification in the number of EPCs. These primary hypothesis-generating data suggest that factors involved in KS, whether hypogonadism, CRFs or other genetically determined factors related to the supernumerary X chromosome might contribute to a reduction in EPCs number and that this could be considered another CRF contributing to the increased mortality of these subjects.

Spermatogenesis in Klinefelter syndrome.

BACKGROUND: Klinefelter syndrome (KS) (47,XXY) is the most common sex chromosomal disorder, and it is a frequent form of male hypogonadism and infertility. Although the majority of these patients are azoospermic, they might have severe oligozoospermia or residual single-residual foci with spermatogenesis in the testis. AIM: We report our experience on sperm retrieval in the ejaculate and testis, and evaluate the frequency of chromosome abnormalities in sperm of KS. SUBJECTS AND METHODS: Eighty-four 47,XXY KS were evaluated with seminal analysis, body hair distribution, reproductive hormones, ultrasonographic scanning of the testis and prostate, bilateral testicular sperm extraction (TESE), sperm or testicular cells sex chromosomes aneuploidies. RESULTS: Out of 84 patients, 7 (7/84; 8.3%) had sperm in the ejaculate. Out of the 77 azoospermic patients, 24 underwent TESE and 9 (9/24; 37.5%) had successful sperm recovery. The comparison of reproductive hormones, age and testicular volume did not show significant differences between patients with and without successful sperm recovery in semen or TESE . Patients without successful sperm recovery in semen analysis or TESE had signs of hypoandrogenism more evident than patients with successful sperm recovery. Patients with KS produced a higher number of sperm aneuploidy with respect to normozoospermic fertile controls and non-genetic severely oligozoospermic men. CONCLUSIONS: Men with KS are not always sterile. In some of these patients sperm can be found in semen or in the testis, but the proportion of sperm aneuploidy is high. Signs of hypoandrogenism seem to be associated with low sperm recovery rate.

Epidemiology, diagnosis, and treatment of male hypogonadotropic hypogonadism.

Hypogonadotropic hypogonadism (HH), or secondary hypogonadism, is a clinical condition due to an impairment of the pituitary function, characterized by low testosterone plasma levels associated with normal or low FSH and LH plasma levels. An impairment of gonadotropin secretion and, therefore, a reduced efficiency of spermatogenesis was reported to be frequently associated to conditions different from the classical causes of secondary hypogonadism. These conditions (metabolic, endocrine and eating disorders, physical exercise etc.) have been associated with a non-classical form of HH that could be called "functional" HH (FHH). FHH differs from the classical one by the evidence that gonadotropin levels are in the low-normal range, but are inadequate for the testosterone levels, that often are also in the low-normal range. This commentary aims at reviewing knowledge on the forms of male HH in order to indicate and discuss clinical context, diagnostic and therapeutic approach in the less known non-classical form, i.e. FHH.

Adrenal morpho-functional alterations in patients with acromegaly.

Acromegaly is associated with a greater morbidity and higher incidence of tumors, possibly due to the permissive role of elevated GH and IGF-I levels. In the general population, adrenal masses are frequently discovered (prevalence 1-5%) at computed tomography (CT). We evaluated the prevalence of adrenal lesions in patients with acromegaly. We studied 94 acromegalic patients, 54 females (mean age 55.0+/-16.0 yr) and 40 males (mean age 50+/-14 yr) referred to 5 Endocrinology Units between 2001-2003; 49 had active disease and 45 had been treated with surgery and/or were controlled with medical therapy. Abdominal CT showed adrenal lesions in 27 patients; 9 of them had unilateral masses (10%) with benign features (diameter 0.5-3 cm) and 18 had hyperplasia (14 monolateral and 4 bilateral), with no significant differences between patients with active vs controlled disease, and with no correlation between prevalence of masses and duration of disease, GH and IGF-I levels. Hormone study (urinary free cortisol, catecholamines/metanephrines, upright plasma renin activity and aldosterone, morning plasma ACTH and low-dose dexamethasone suppression test) disclosed no major endocrine alterations. During a 1-yr follow-up, the adrenal masses increased in size in 3 cases and 1 patient also developed subclinical Cushing's syndrome. Adrenal lesions seem more frequent in acromegaly than in the general population, but no single factor (GH/IGF-I levels or disease duration) predicts them. The masses appear to be benign and nonhypersecreting, but a longer follow-up is recommended to disclose any changes in their morphofunctional state.

Hormonal treatment of male infertility: FSH.

FSH plays a crucial role in spermatogenesis. In the fetal and neonatal development stages, FSH activates the proliferation of the Sertoli cells and successively, during the pubertal phase, it influences the mitotic activity of the spermatogonia and encourages cellular differentiation, until arrival at the round spermatid stage. Because of its physiological role in spermatogenesis, various attempts have been made to treat idiopathic oligozoospermic men with FSH. However, the results obtained so far are still controversial. In this research, attention was focused on the possible criteria able to predict a seminal response to this specific hormonal treatment. Furthermore, the effectiveness of FSH therapy was evaluated in terms of sperm count and pregnancy rate. Thus far, based on more recent knowledge about the FSH receptor gene, the authors have correlated different polymorphisms of this gene with the outcome of FSH treatment. In this paper, the literature is reviewed and the authors' experience on using FSH in male infertility is discussed.

Y chromosome haplogroups and susceptibility to testicular cancer.

Although in the past decades much progress in testicular cancer (TC) management has been made, little is known about the possible genetic causes and molecular mechanisms involved in its aetiopathogenesis. Some studies on possible contribution of the Y chromosome in TC development have been previously published, but data are not conclusive. In particular, ethnic influence and spermatogenic activity of patients with TC have not been adequately considered in previous studies, although they may represent important confounding factors. The objective of this study is to analyse the contribution of the Y chromosome in testicular germ cell cancer subjects who are well defined at the microgeographical, clinical and seminological level. We analysed Y chromosome classic azoospermia factor (AZF) deletions, partial AZFc deletions and Y haplogroups in 118 sporadic cases of testicular germ cell cancer and 93 microgeographically matched controls. Y chromosome screening failed to identify Y chromosome microdeletions in either cases or controls. Y chromosome haplogroup distribution and frequencies did not differ between cases and controls. Furthermore, no difference was observed when comparing patients with seminoma and non-seminoma, nor when comparing patients with TC with normozoospermia and azoo-oligozoospermia. Our findings combined with data reported so far suggest that classic AZF deletions and partial AZFc deletions are not a frequent cause or risk factor for TC and that different Y haplogroup distribution does not contribute to susceptibility to this tumour.

Paracrine and endocrine roles of insulin-like factor 3.

Insulin-like factor 3 (INSL3) is expressed in Leydig cells of the testis and theca cells of the ovary. This peptide affects testicular descent by acting on gubernaculum via its specific receptor leucine-rich repeat-containing G protein-coupled receptor 8 (LGR8). From initial animal data showing the cryptorchid phenotype of Insl3/Lgr8 mutants, an extensive search for mutations in INSL3 and LGR8 genes was undertaken in human patients with cryptorchidism, and a frequency of mutation of 4-5% has been detected. However, definitive proofs of a causative role for some of these mutations are still lacking. More recent data suggest additional paracrine (in the testis and ovary) and endocrine actions of INSL3 in adults. INSL3 circulates at high concentrations in serum of adult males and its production is dependent on the differentiation effect of LH. Therefore, INSL3 is increasingly used as a specific marker of Leydig cell differentiation and function.

Age-matched cavernous peak systolic velocity: a highly sensitive parameter in the diagnosis of arteriogenic erectile dysfunction.

Recently it has been reported that there is a strict correlation between erectile dysfunction (ED) and cardiovascular diseases, but the importance of such relationship still needs to be addressed. Ultrasonographic peak systolic velocity (PSV), is considered a reliable parameter for the diagnosis of arteriogenic ED. However, the cut-off value of PSV<30 cm/s has sufficient sensitivity only in the diagnosis of advanced arteriogenic ED and it is not representative of peripheral vascular alterations. In the present study, we set up an age-adjustment of PSV - calculated with the formula PSV <6.73+age x 0.7 - that permits a more accurate diagnosis of vascular aetiology in ED patients and may predict the presence of carotid wall alterations. We studied 179 consecutive subjects (mean age 52 years, range 23-79 years), with a history of ED of at least 6 months, by means of penile colour doppler ultrasonography (P-CDU) and common carotid arteries colour doppler ultrasonography (CCA-CDU) between June 2003 and September 2004. Statistical analysis was carried out with the statistical software R. PSV and CCAD values showed a statistically significant negative correlation. Age adjustment further improved this relationship permitting to identify an age-dependent PSV cut-off given by the formula PSV <6.73+age x 0.7. The age-adjusted PSV cut-off allows an accurate interpretation of vascular aetiology in ED patients and predicts the presence of carotid wall alterations, from the intima-media pathologic thickness to the plaque formation, with high values of both sensitivity and specificity.