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ABSTRACT: Olfactory receptor (OR) expression is also present in the sperm cells and could mediate sperm chemotaxis. OR1D2 was the first OR expressed in the testis demonstrated to be involved in chemotaxis and to be expressed also in the nose with a similar behavior. Bourgeonal is the OR1D2 most potent known agonist. Infertility affects ~15 % of couples in western countries and sometimes it is unexplained. This pilot study compared the bourgeonal olfactory thresholds, the ability of sperm to sense the bourgeonal and the frequency of 13 single nucleotide polymorphisms (SNPs) of OR1D2 gene in nine males suffering of unexplained infertility with a control group of 15 healthy males. The mean olfactory threshold for bourgeonal was statistically different between the study group (10.5 ± 3.7; median 12.3) and the control group (14.0 ± 2.8; median 15.5) (p = 0.006). Statistical analysis showed a significantly higher percentage of spermatozoa that migrated toward the capillaries filled with bourgeonal in the control group compared to the study group (p < 0.0001). Sperm migration was equally inhibited in both groups of subjects when, together with bourgeonal, capillaries were filled with undecanal, a strong bourgeonal inhibitor (p = 0.42). The 13 SNPs of OR1D2 revealed a statistically significant difference for allele and genotype frequency of rs769423 in study group versus control group (p = 0.02). The present preliminary study seems to confirm the important role of OR1D2 both in nose and spermatozoa and may explain the idiopathic infertility of the study group. Further studies on larger series are mandatory to confirm our preliminary evidence.
European archives of oto-rhino-laryngology. Supplement 03/2013;
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ABSTRACT: Background: Although vascular-calcification mechanisms are only partially understood, the role of circulating calcifying cells and non-collagenous bone matrix proteins in the bone-vascular axis is emerging. Despite that platelets represent a cellular interface between hemostasis, inflammation, and atherosclerosis and have a myeloid precursor, a possible involvement in the modulation of vascular calcification has been rarely investigated. We investigated if osteocalcin (OC) is released by platelets and described OC expression in patients with carotid artery occlusive disease. Methods: Expression and release of OC were determined by Western blot, immunofluorescence, FACS, and ELISA in human resting and activated platelets and megakaryocytes. Co-localization of platelet aggregates, macrophages, OC, and calcifications was studied in carotid endoarterectomy specimens and normal tissues. Results: Human platelets expressed OC and co-localized with CD63 in δ-granules. Upon activation with an endogenous mechanism, platelets released OC in the extracellular medium. Expression of OC in megakaryocytes suggested a lineage specificity. OC count in circulating platelets and the released amount were significantly higher in patients with carotid artery occlusive disease than in healthy controls (P<0.0001) despite similar serum levels. In atherosclerotic plaques OC strongly overlapped with CD41+ platelets in the early stage of calcification, but this wass not seen in normal tissues. CD68+OC+ cells were present at the periphery of the calcified zone. Conclusions: Given the active role played by platelets in the atherosclerotic process, the involvement of OC release from platelets in atherosclerotic lesions and the impact of genetic and cardiovascular risk factors in mediating bone-marrow preconditioning should be investigated further. © 2012 International Society on Thrombosis and Haemostasis.
Journal of Thrombosis and Haemostasis 12/2012; · 5.73 Impact Factor
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ABSTRACT: 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 LH6 dependency of Vitamin D 25- hydroxylation. Subjects and methods: 125 normotestosteronemic patients with testicular cancer, 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.
Journal of endocrinological investigation 10/2012; · 1.57 Impact Factor
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Osteoporosis International 09/2012; · 4.58 Impact Factor
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ABSTRACT: Background Relationships between anthropometric measures, body proportions, weight and penile dimensions in young adult males have not been previously analysed. Furthermore, although male fertility declined in last decades, no data on testicular volume (the best surrogate measure for spermatogenic potential) is available for the general population of young men in Italy. Aim To analyze for anthropometric measures and proportions, testicular volumes, and penile dimensions a large cohort from the general population of young Italian men aged 18-19 years. Materials/subject We analysed 2019 students aged 18-19 years for height, weight, body mass index (BMI), waist circumference, arm span, pubis-to-floor and crown-to-pubis length, and penile dimensions. Testicular volumes were measured by ultrasound in 776 subjects. Results Subjects with a pathological arm span - height (>3 cm) were 36.0% and those with a pathological pubis-to-floor/crown-to-pubis ratio (≤0.92) were 44.7%. The mean penis length was 8.9 ± 1.4 cm and the penis circumference was 9.5 ± 1.0 cm. BMI was positively associated with arm span - height difference and negatively with penis length. The rate of subjects with low mean testicular volume (<12 mL) was 23.2%. Conclusions The findings highlight a strong influence of BMI on skeletal proportions and penis length, identify a large proportion of subjects with testicular hypotrophy at risk for future fertility, and suggest to consider worldwide studies to redefine normal values for arm span - height and upper/lower body segment ratio.
Journal of endocrinological investigation 07/2012; · 1.57 Impact Factor
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ABSTRACT: 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.
International Journal of Andrology 04/2012; 35(5):720-5. · 3.59 Impact Factor
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ABSTRACT: An excess of adipose tissue (AT) in obese individuals is linked to increased cardiovascular risk and mitochondria have been shown to be defective in the muscle and AT of patients with metabolic disorders such as obesity and Type 2 diabetes. Nitric oxide (NO) generated by endothelial NO synthase (eNOS) plays a role in mitochondrial biogenesis through cyclic-GMP (cGMP). AT harbors the whole molecular signaling pathway of NO, together with type 5-phosphodiesterase (PDE- 5), the main cGMP catabolising enzyme.
Our aim was to evaluate the effect of the modulation of NO pathway, through PDE-5 inhibition, on energy metabolism and mitochondria biogenesis in human omental AT.
Cultured human omental AT was stimulated with PDE-5 inhibitor, vardenafil, at different concentration for 24 and 72 h. Analysis of the expression of both key-regulator genes of adipocyte metabolism and mitochondria-biogenesis markers was performed.
We found an increased gene expression of peroxisome proliferator-activated receptor-γ (PPAR-γ), adiponectin, and proliferator- activated receptor gamma coactivator-1 α (PGC-1α) after a 24-h stimulation with vardenafil at the lowest concentration employed compared to controls (p<0.05). After 72 h of stimulation, a significant increase of mitochondrial DNA was found compared to control samples (p<0.05).
Our data suggest that PDE-5 inhibition could have an impact on mitochondrial content of human AT suggesting a positive effect on energy metabolism and adding new elements in the comprehension of AT pathophysiology.
Journal of endocrinological investigation 11/2011; 34(10):738-41. · 1.57 Impact Factor
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ABSTRACT: 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.
International Journal of Andrology 08/2011; 34(4):306-12. · 3.59 Impact Factor
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ABSTRACT: 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.
International Journal of Andrology 07/2011; 34(6 Pt 2):e511-7. · 3.59 Impact Factor
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ABSTRACT: Human papilloma virus (HPV) infection is very common worldwide, but the actual incidence and significance of HPV infection in sperm are poorly understood. In this study, we evaluated the presence of HPV in spermatozoa from thawed semen samples previously stored in our sperm bank. We performed polymerase chain reaction and in situ hybridization for HPV detection in cryovials belonging to 98 oncology patients and in 60 semen samples from healthy controls. Statistical analysis was performed by two-tailed Student's t-test and Fisher's exact test. The frequency of HPV semen infection was 6.1% in thawed cryovials from patients and 3.3% in semen samples from controls. Among the patients, four were found positive for high-risk HPV, one for medium-risk HPV and another for low-risk HPV. Patients had a significantly higher percentage of infected sperm than controls. In conclusion, this report shows the presence of HPV in sperm cells from cryovials of a sperm bank. It is still unclear if HPV-infected sperm are able to cross-contaminate cryovials and impair the outcome of assisted reproduction techniques or to infect partners. Further studies are needed to understand whether screening for HPV should be performed in all semen samples before sperm banking or before intra-cytoplasmic sperm injection procedures.
International Journal of Andrology 06/2011; 34(3):242-6. · 3.59 Impact Factor
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ABSTRACT: For fertilization to occur in mammals, ejaculated spermatozoa must reach the egg which, following ovulation has moved from the ovary into the Fallopian tube. Two active mechanisms of spermatozoa guidance have been shown in mammals: thermotaxis and chemotaxis. The identity of most of human spermatozoa chemoattractants is unknown, and herein we tested if SDF1 (chemokine stromal cell-derived factor-1) and its pathway is involved in spermatozoa chemotaxis. We found that SDF1 is expressed in the oocytes, endometrium and follicular fluid, as well as its specific receptor CXCR4 (chemokine CXC motif receptor 4) is expressed in the head of spermatozoa. By SDF1 gradient experiments, we stated that SDF1 is able to induce hyperactivation in spermatozoa leading to accumulation, to give rise to an increase in intracellular calcium concentration, and to preserve the mitochondrial status and not to induce acrosome reaction. Our findings suggest these phenomena could reflect spermatozoa chemotaxis, and that SDF1 action could represent an important event leading to egg fertilization, even if further studies regarding the link between spermatozoa accumulation and chemotaxis are mandatory. These data suggest that the SDF-1/CXCR4 signalling could be used to manipulate the human fertilization, to improve both the outcome of physiological or assisted reproduction, and to develop new contraceptive methods, by development of SDF1 or CXCR4 antagonist.
International Journal of Andrology 05/2011; 34(6 Pt 2):e554-65. · 3.59 Impact Factor
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Osteoporosis International 05/2011; 22(5):1643-4. · 4.58 Impact Factor
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ABSTRACT: Different mechanisms in Klinefelter syndrome contribute to reduced bone mass and osteoporosis, which have a precocious onset and are detected in up to 40% of patients, irrespectively of testosterone levels. Androgen receptor, X chromosome inactivation and INSL3 levels are hypothesized to cooperate with and modulate the effect of testosterone on the bone. CONCLUSION: New perspectives on genetic topics are opening exciting areas of research on the pathophysiology of reduced bone mass in Klinefelter patients.
Acta Paediatrica 01/2011; 100(6):878-84. · 2.07 Impact Factor
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ABSTRACT: Nearly 70 years after its description, Klinefelter syndrome (KS) remains a largely undiagnosed condition. As its clinical presentation may be subtle, many of those affected may be unaware or diagnosed only during evaluation for hypogonadism and/or infertility. In February 2010 an interdisciplinary panel of specialists met in Abano Terme (Padua, Italy) in a workshop on "Klinefelter Syndrome: diagnosis and clinical management". The main aim of this meeting was to discuss several aspects related to the epidemiology, pathogenesis, and evaluation of KS and to develop a consensus defining its early diagnosis and treatment. In the present consensus we have highlighted the features that may prompt the physicians to look after patients with KS both for the syndrome and correlated diseases. We have provided evidences that, during the different phases of life, there might be some advantages in establishing the diagnosis and starting proper follow-up and treatment. The workshop was carried out under the auspices of the Italian Society of andrology and Sexual Medicine (SIAMS).
Journal of endocrinological investigation 12/2010; 33(11):839-50. · 1.57 Impact Factor
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ABSTRACT: The paper entitled "Expression of phosphodiesterase type 5A in human spermatozoa and influence of its inhibition on motility and functional sperm parameters" by C. Foresta et al, which was published online on 1 July 2010, has been withdrawn at the authors' request.
Journal of endocrinological investigation 07/2010; · 1.57 Impact Factor
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ABSTRACT: 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.
Molecular Human Reproduction 03/2010; 16(6):411-7. · 3.85 Impact Factor
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ABSTRACT: Hypogonadism represents one of the most important causes of male osteoporosis. Testosterone regulates male bone metabolism both indirectly by aromatization to estrogens and directly through the androgen receptor (AR) on osteoblasts, promoting periosteal bone formation during puberty and reducing bone resorption during adult life. Early onset of testosterone deficiency, as observed in Klinefelter's syndrome (KS), is an important risk factor for precocious osteoporosis. Osteoporosis is present in up to 40% of subjects with KS and has usually been attributed to low testosterone levels. However, reduced bone mass might be present also in KS men with normal testosterone levels and testosterone replacement therapy does not always restore bone density in KS patients. Possible new determinants for osteoporosis in KS might be related to the AR function and insulin-like factor 3 (INSL3) levels. The CAG length and inactivation pattern of the AR in KS have been related to osteoporosis, but definitive proof is lacking. INSL3 has an anabolic role on bone metabolism by acting on osteoblasts and INSL3 levels are low in KS. Therefore, low INSL3 concentrations might represent a possible new pathogenic mechanism for reduced bone mass in KS.
Molecular Human Reproduction 03/2010; 16(6):402-10. · 3.85 Impact Factor
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ABSTRACT: 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.
We report our experience on sperm retrieval in the ejaculate and testis, and evaluate the frequency of chromosome abnormalities in sperm of KS.
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.
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.
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.
Journal of endocrinological investigation 03/2010; 33(11):789-93. · 1.57 Impact Factor
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A Lenzi,
G Balercia,
A Bellastella,
A Colao,
A Fabbri, C Foresta,
M Galdiero,
L Gandini,
C Krausz,
G Lombardi,
F Lombardo,
M Maggi,
A Radicioni,
R Selice,
A A Sinisi,
G Forti
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ABSTRACT: 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.
Journal of endocrinological investigation 12/2009; 32(11):934-8. · 1.57 Impact Factor
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ABSTRACT: Clinical investigation of canine testicular function is complicated by the difficulty in the evaluation of seminiferous tubules. Until recently, testicular biopsy was the only diagnostic option for dogs with persistent oligo/azoospermia. In human andrology, testicular fine needle aspiration (TFNA) is currently considered a useful method in the evaluation of azoospermia and severe oligozoospermia, and has long replaced classical biopsy to evaluate spermatogenesis. In order to verify its diagnostic efficacy for the clinical approach to canine oligo- or azoospermia, TFNA was performed in seven adult (two oligozoospermic and five azoospermic) dogs. After sedation, a fine (21-23 gauge) butterfly needle connected to a 50-ml syringe was inserted into each testicle; strong suction was applied and the aspirated fluid squirted on a glass slide, smeared out, air-dried and stained with a modified May-Grunwald-Giemsa. Under light microscopy, Sertoli cells (all those found in each investigated field) and spermatogenic cells (n = 100) were counted on each smear in order to differentiate spermatogonia, primary spermatocytes, secondary spermatocytes, early spermatids, late spermatids and spermatozoa, and calculate their relative percentages. Cytological analysis showed the following testicular pictures: normal spermatogenesis (compatible with obstruction of the seminal ducts), hypospermatogenesis, maturative disturbances and Sertoli cell-only syndrome. Two dogs with an obstructive lesion were treated with corticosteroids; one of them recovered and sired two litters of puppies.
Reproduction in Domestic Animals 07/2009; 44 Suppl 2:329-33. · 1.36 Impact Factor
