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Biomedical subjects

Carlo Foresta

Publications and source records attributed to Carlo Foresta.

31 records · Page 2Linked to original sources
PubMed2004

Analysis of the DAZ gene family in cryptorchidism and idiopathic male infertility.

OBJECTIVE: To investigate whether partial deletions of the DAZ gene family on the Y chromosome are associated with cryptorchidism, similar to that found for complete AZF deletions. DESIGN: Prospective study. SETTING: University hospital. PATIENT(S): A total of 193 azoospermic and severely oligozoospermic men: 95 with a history of cryptorchidism and 98 classified as idiopathic. INTERVENTION(S): A two-part study for Y chromosome microdeletions was performed: a polymerase chain reaction (PCR)-based analysis for complete AZF deletions and partial DAZ gene analysis by PCR-restriction digestion assay for single-family variants. MAIN OUTCOME MEASURE(S): Presence and type of AZF deletions and number of DAZ genes present. RESULT(S): The frequency of complete AZF deletions was similar in idiopathic (13.3%) and cryptorchid men (11.6%), but partial DAZ deletions were found only in infertile subjects without cryptorchidism (7.1%). The testicular phenotype was similar in men with complete AZF deletions and partial DAZ deletions, therefore the contribution of the other AZF genes in determining the spermatogenic impairment is still unclear. CONCLUSION(S): Our findings suggest that the loss of only some copies of DAZ is sufficient to lead to severe male infertility, but it is not a frequent finding in cryptorchid men.

Chromosomes, Human, Y↗
PubMed2004

Role of INSL3 and LGR8 in cryptorchidism and testicular functions.

Cryptorchidism is the most frequent congenital anomaly of the urogenital tract in human males. INSL3 and LGR8/GREAT proteins seem to act as ligand and receptor respectively, and to have a role in gubernaculum development involved in testicular descent. Mutations in the INSL3 gene or LGR8/GREAT were found to be associated with cryptorchidism in humans. In a cohort of 135 ex-cryptorchid patients and 100 controls, mutations were sought in INSL3 and LGR8/GREAT genes by sequencing. Six patients were found with mutations in the INSL3 gene and four patients with LGR8/GREAT mutation (10/135, 7.4%). The 10 patients show different phenotypes, ranging from normozoospermia to complete azoospermia, and from bilateral cryptorchidism to retractile testes. Furthermore, the endocrine function of the testis appeared normal in all subjects. These findings demonstrate that INSL3-LGR8/GREAT mutations are frequently associated with human cryptorchidism, and that the only clinical consequence of alterations of the INSL3-LGR8/GREAT system seems to be failure of the testis to descend normally in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself. The first analysis in humans of INSL3 was then performed using a novel radioimmunoassay kit to measure INSL3 concentrations in serum of adults. The results show that INSL3 circulates in adult men, it is a male-specific hormone, and it is of almost exclusively testicular origin. The role of this hormonal system in adulthood is, however, to date unknown.

Adult↗
PubMed2004

A novel circulating hormone of testis origin in humans.

Insulin-like factor 3 (INSL3) is a member of the relaxin-insulin family, and it is expressed in pre- and postnatal Leydig cells of the testis. This peptide affects testicular descent during embryonic development, and mutations in INSL3 gene or its receptor LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8)/GREAT (G protein-coupled receptor affecting testicular descent) cause cryptorchidism in humans. The expression of LGR8/GREAT in different tissues and the production of INSL3 also by adult-type Leydig cells suggest additional roles of this hormonal system in adulthood. In this preliminary report we performed the first analysis in humans of INSL3 using a novel RIA kit to measure INSL3 concentrations in serum of normal men and with different testicular pathologies. The results show that INSL3 is circulating in adult men, and it is almost exclusively of testicular origin. Subjects with severe testicular damage, such as men with severe infertility, produce low amount of INSL3, and the concentrations of this hormone seem to reflect the functional status of the Leydig cells. In particular, INSL3 concentrations may be an even more sensitive marker of Leydig cell function than testosterone itself. Analysis of men treated with different combinations of hormones of the hypothalamus-pituitary-testis axis suggests that the production of INSL3 is related to LH in a manner similar to that of the LH-testosterone axis.

Adult↗
PubMed2004

Homeobox HOXA10 gene analysis in cryptorchidism.

BACKGROUND: In male mice, targeted disruption of the homeobox gene hoxa10 causes cryptorchidism and infertility. Genetic alterations in exon 1 of HOXA10 have been found in a high number of boys with cryptorchidism. AIM: To evaluate whether mutations of HOXA10 can be a common cause of cryptorchidism. PATIENTS AND METHODS: Genomic DNA was extracted from 18 patients with cryptorchidism (age 7-44 years; unilateral n = 13; no familial cases) and 28 healthy controls (age 9-39 years). HOXA10 was amplified by PCR and all coding sequences of exon 1 and 2 were sequenced. The PCR products were digested by ScrFI restriction enzyme and the restriction fragments obtained were analyzed on 2% agarose gel. RESULTS: One silent polymorphism, G-->A substitution at position 1203, was detected in 2/18 patients (11.1%). The same polymorphism was detected in 3/28 controls (10.7%). CONCLUSIONS: These data on HOXA10 analysis indicate that alterations of this gene may be more rare in males with cryptorchidism than previously suggested. This finding agrees with the rare occurrence of INSL3 gene mutations in human cryptorchidism, but needs to be confirmed in a larger series of selected patients.

Adolescent↗
PubMed2003

The INSL3-LGR8/GREAT ligand-receptor pair in human cryptorchidism.

Testicular descent is a complex multistep embryonic process requiring the interaction between anatomical and hormonal factors. Failure in any of these steps results in cryptorchidism, the most frequent congenital anomaly of the urogenital tract in human males. Evidence for a genetic cause for cryptorchidism is numerous and supported by animal models. In particular, INSL3 and LGR8/GREAT proteins seem to act as ligand and receptor, respectively, and to have a role in gubernaculum development involved in testicular descent. In a cohort of 87 ex-cryptorchid patients and 80 controls, we looked for mutations in INSL3 and LGR8/GREAT genes by sequencing. Patients were classified on the basis of seminal, hormonal, and testicular cytological analyses. We found three mutations in the INSL3 gene in four patients and one LGR8/GREAT mutation in four patients (8 of 87, 9.2%). The eight patients show different phenotypes, ranging from normozoospermia to complete azoospermia, and from bilateral cryptorchidism to retractile testes. Furthermore, the endocrine function of the testis appears normal in all subjects. The findings of our study demonstrate that INSL3-LGR8/GREAT mutations are frequently associated with human cryptorchidism and are maternally inherited. The only clinical consequence of alterations of the INSL3-LGR8/GREAT system seems to be failure of the testis to normally descend in the scrotum during embryonic development, without affecting the spermatogenic and endocrine components of the testis itself.

Adult↗
PubMed2002

Genetic variations of gpx-4 and male infertility in humans.

Phospholipid hydroperoxide glutathione peroxidase (PHGPx), the product of gpx-4, is the major selenoprotein in sperm and is considered essential for fertilization because of its multiple roles in spermatogenesis, such as hydroperoxide detoxification, formation of the mitochondrial capsule, and chromatin condensation. Genomic DNA sequences of 3.148 kilobases covering the whole gpx-4 and its flanking regions were amplified from 63 men using the polymerase chain reaction and were analyzed for polymorphisms by direct sequencing. A total of 23 variant sites were detected; 2 were present only in control men (proven fathers; n = 21) and 10 were common to fertile controls and infertile patients (n = 42). A further 11 variant sites were seen in five of the infertile men only. Four of the gpx-4 variants were considered irrelevant to GPx-4-related fertility problems because they occurred homozygously in controls. The majority of the remaining variant sites are also of questionable relevance because they are located in introns or, as third base exchanges, do not affect the protein sequence. However, one of the exon variations leads to an Ala93-Thr exchange that reduces activity in a porcine GPx-4 homologue. Two detected promoter variations were shown by reporter gene constructs to affect transcription in somatic cell lines. These results indicate that gpx-4 polymorphism cannot generally account for the correlation of PHGPx content of sperm and fertility-related parameters, but further examination of this gene as a potential cause of infertility in particular cases is warranted.

Alanine↗
PubMed2002

Use of recombinant human follicle-stimulating hormone in the treatment of male factor infertility.

OBJECTIVE: To evaluate the effects of treatment with recombinant human FSH (r-hFSH) on seminal parameters and seminiferous epithelium in idiopathic patients with oligozoospermia with normal FSH plasma levels. DESIGN: Randomized single-blind study. SETTING: Academic setting. PATIENT(S): Forty-five subjects with idiopathic oligozoospermia (sperm count <10 x 10(6)/mL) and normal FSH and inhibin B plasma levels. INTERVENTION(S): Three months of treatment with r-hFSH 50 IU (15 patients) or with r-hFSH 100 IU on alternate days (15 patients) or no treatment (15 patients); bilateral testicular fine-needle aspiration (FNA) performed before and after therapy; FSH and inhibin B plasma levels evaluated during treatment. MAIN OUTCOME MEASURE(S): Seminal parameters; testicular cytological features evaluated by FNA; plasma levels of FSH, LH, T, and inhibin B. RESULT(S): Treatment with r-hFSH at a dose of 50 IU induced no increase in sperm concentration, while treatment with r-hFSH at a dose of 100 IU induced a significant increase in sperm concentration. In particular, in 11/15 patients a doubling of the pretreatment sperm concentration was observed. No significant increase in sperm parameters was observed in the control group. In both groups of patients treated with r-hFSH, the cytological analysis before treatment showed hypospermatogenesis. An increase in the percentage of spermatogonia and spermatocytes was observed only after the treatment with r-hFSH at a dose of 100 IU. CONCLUSION(S): The findings of this study demonstrate that r-hFSH at a dose of 100 IU, as previously seen with highly purified FSH, increases the spermatogonial population and sperm production in idiopathic patients with oligozoospermia with normal FSH and inhibin B plasma levels and a cytological picture of hypospermatogenesis.

Biopsy, Needle↗
PubMed2002

Guidelines for the appropriate use of genetic tests in infertile couples.

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.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2002

Male fertility is linked to the selenoprotein phospholipid hydroperoxide glutathione peroxidase.

The selenoprotein phospholipid hydroperoxide glutathione peroxidase (PHGPx) accounts for almost the entire selenium content of mammalian testis. PHGPx is abundantly expressed in spermatids as active peroxidase but is transformed to an oxidatively inactivated protein in mature sperm, where it is a major constituent of the mitochondrial capsule in the midpiece. Male infertility in selenium-deficient animals, which is characterized by impaired sperm motility and morphological midpiece alterations, is considered to result from insufficient PHGPx content. We studied the relationship between sperm PHGPx, measured as rescued activity, and human fertility. Sperm specimens from 75 infertile men and 37 controls were analyzed for fertility-related parameters according to World Health Organization criteria. The PHGPx protein content was estimated after reductive solubilization of the spermatozoa by measuring the rescued PHGPx activity. Rescued PHGPx activity of infertile men ranged significantly below that of controls (93.2 +/- 60.1 units/mg sperm protein vs. 187.5 +/- 55.3 units/mg) and was particularly low in oligoasthenozoospermic specimens (61.93 +/- 45.42 units/mg; P < 0.001 compared with controls and asthenozoospermic samples). Rescued PHGPx activity was correlated positively with viability, morphological integrity, and most profoundly forward motility (r = 0.35, 0.44, and 0.45, respectively). In isolated motile samples, motility decreased faster with decreasing PHGPx content. In humans, PHGPx appears to be indispensable for structural integrity of spermatozoa and to codetermine sperm motility and viability. Because the content of PHGPx, irrespective of the cause of alteration, is correlated with fertility-related parameters, PHGPx can be considered a predictive measure for fertilization capacity.

Adult↗
PubMed2002

Inhibin B plasma concentrations in infertile patients with DAZ gene deletions treated with FSH.

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.

Adult↗
PubMedDate not supplied

[Clinical and diagnostic approach to erectile dysfunction].

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.

Algorithms↗